Viral manipulation of STAT3: Evade, exploit, and injure
Identifieur interne : 001158 ( Pmc/Corpus ); précédent : 001157; suivant : 001159Viral manipulation of STAT3: Evade, exploit, and injure
Auteurs : Armando Andres Roca Suarez ; Nicolaas Van Renne ; Thomas F. Baumert ; Joachim LupbergerSource :
- PLoS Pathogens [ 1553-7366 ] ; 2018.
Abstract
Signal transducer and activator of transcription 3 (STAT3) is a key regulator of numerous physiological functions, including the immune response. As pathogens elicit an acute phase response with concerted activation of STAT3, they are confronted with two evolutionary options: either curtail it or employ it. This has important consequences for the host, since abnormal STAT3 function is associated with cancer development and other diseases. This review provides a comprehensive outline of how human viruses cope with STAT3-mediated inflammation and how this affects the host. Finally, we discuss STAT3 as a potential target for antiviral therapy.
Url:
DOI: 10.1371/journal.ppat.1006839
PubMed: 29543893
PubMed Central: 5854428
Links to Exploration step
PMC:5854428Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Viral manipulation of STAT3: Evade, exploit, and injure</title><author><name sortKey="Roca Suarez, Armando Andres" sort="Roca Suarez, Armando Andres" uniqKey="Roca Suarez A" first="Armando Andres" last="Roca Suarez">Armando Andres Roca Suarez</name><affiliation><nlm:aff id="aff001"><addr-line>Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Université de Strasbourg, Strasbourg, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Van Renne, Nicolaas" sort="Van Renne, Nicolaas" uniqKey="Van Renne N" first="Nicolaas" last="Van Renne">Nicolaas Van Renne</name><affiliation><nlm:aff id="aff001"><addr-line>Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Université de Strasbourg, Strasbourg, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Baumert, Thomas F" sort="Baumert, Thomas F" uniqKey="Baumert T" first="Thomas F." last="Baumert">Thomas F. Baumert</name><affiliation><nlm:aff id="aff001"><addr-line>Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Université de Strasbourg, Strasbourg, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff003"><addr-line>Pôle Hépato-digestif, Institut Hospitalo-universitaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lupberger, Joachim" sort="Lupberger, Joachim" uniqKey="Lupberger J" first="Joachim" last="Lupberger">Joachim Lupberger</name><affiliation><nlm:aff id="aff001"><addr-line>Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Université de Strasbourg, Strasbourg, France</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">29543893</idno><idno type="pmc">5854428</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854428</idno><idno type="RBID">PMC:5854428</idno><idno type="doi">10.1371/journal.ppat.1006839</idno><date when="2018">2018</date><idno type="wicri:Area/Pmc/Corpus">001158</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001158</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Viral manipulation of STAT3: Evade, exploit, and injure</title><author><name sortKey="Roca Suarez, Armando Andres" sort="Roca Suarez, Armando Andres" uniqKey="Roca Suarez A" first="Armando Andres" last="Roca Suarez">Armando Andres Roca Suarez</name><affiliation><nlm:aff id="aff001"><addr-line>Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Université de Strasbourg, Strasbourg, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Van Renne, Nicolaas" sort="Van Renne, Nicolaas" uniqKey="Van Renne N" first="Nicolaas" last="Van Renne">Nicolaas Van Renne</name><affiliation><nlm:aff id="aff001"><addr-line>Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Université de Strasbourg, Strasbourg, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Baumert, Thomas F" sort="Baumert, Thomas F" uniqKey="Baumert T" first="Thomas F." last="Baumert">Thomas F. Baumert</name><affiliation><nlm:aff id="aff001"><addr-line>Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Université de Strasbourg, Strasbourg, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff003"><addr-line>Pôle Hépato-digestif, Institut Hospitalo-universitaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Lupberger, Joachim" sort="Lupberger, Joachim" uniqKey="Lupberger J" first="Joachim" last="Lupberger">Joachim Lupberger</name><affiliation><nlm:aff id="aff001"><addr-line>Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff002"><addr-line>Université de Strasbourg, Strasbourg, France</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS Pathogens</title><idno type="ISSN">1553-7366</idno><idno type="eISSN">1553-7374</idno><imprint><date when="2018">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Signal transducer and activator of transcription 3 (STAT3) is a key regulator of numerous physiological functions, including the immune response. As pathogens elicit an acute phase response with concerted activation of STAT3, they are confronted with two evolutionary options: either curtail it or employ it. This has important consequences for the host, since abnormal STAT3 function is associated with cancer development and other diseases. This review provides a comprehensive outline of how human viruses cope with STAT3-mediated inflammation and how this affects the host. Finally, we discuss STAT3 as a potential target for antiviral therapy.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Akira, S" uniqKey="Akira S">S Akira</name></author><author><name sortKey="Nishio, Y" uniqKey="Nishio Y">Y Nishio</name></author><author><name sortKey="Inoue, M" uniqKey="Inoue M">M Inoue</name></author><author><name sortKey="Wang, Xj" uniqKey="Wang X">XJ Wang</name></author><author><name sortKey="Wei, S" uniqKey="Wei S">S Wei</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mackey Lawrence, Nm" uniqKey="Mackey Lawrence N">NM Mackey-Lawrence</name></author><author><name sortKey="Petri, Wa" uniqKey="Petri W">WA Petri</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wilks, Af" uniqKey="Wilks A">AF Wilks</name></author><author><name sortKey="Harpur, Ag" uniqKey="Harpur A">AG Harpur</name></author><author><name sortKey="Kurban, Rr" uniqKey="Kurban R">RR Kurban</name></author><author><name sortKey="Ralph, Sj" uniqKey="Ralph S">SJ Ralph</name></author><author><name sortKey="Zurcher, G" uniqKey="Zurcher G">G Zurcher</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rane, Sg" uniqKey="Rane S">SG Rane</name></author><author><name sortKey="Reddy, Ep" uniqKey="Reddy E">EP Reddy</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Firmbach Kraft, I" uniqKey="Firmbach Kraft I">I Firmbach-Kraft</name></author><author><name sortKey="Byers, M" uniqKey="Byers M">M Byers</name></author><author><name sortKey="Shows, T" uniqKey="Shows T">T Shows</name></author><author><name sortKey="Dalla Favera, R" uniqKey="Dalla Favera R">R Dalla-Favera</name></author><author><name sortKey="Krolewski, Jj" uniqKey="Krolewski J">JJ Krolewski</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kaptein, A" uniqKey="Kaptein A">A Kaptein</name></author><author><name sortKey="Paillard, V" uniqKey="Paillard V">V Paillard</name></author><author><name sortKey="Saunders, M" uniqKey="Saunders M">M Saunders</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Delgoffe, Gm" uniqKey="Delgoffe G">GM Delgoffe</name></author><author><name sortKey="Vignali, Da" uniqKey="Vignali D">DA Vignali</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wen, Z" uniqKey="Wen Z">Z Wen</name></author><author><name sortKey="Zhong, Z" uniqKey="Zhong Z">Z Zhong</name></author><author><name sortKey="Darnell, Je" uniqKey="Darnell J">JE Darnell</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wegrzyn, J" uniqKey="Wegrzyn J">J Wegrzyn</name></author><author><name sortKey="Potla, R" uniqKey="Potla R">R Potla</name></author><author><name sortKey="Chwae, Yj" uniqKey="Chwae Y">YJ Chwae</name></author><author><name sortKey="Sepuri, Nb" uniqKey="Sepuri N">NB Sepuri</name></author><author><name sortKey="Zhang, Q" uniqKey="Zhang Q">Q Zhang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yuan, Zl" uniqKey="Yuan Z">ZL Yuan</name></author><author><name sortKey="Guan, Yj" uniqKey="Guan Y">YJ Guan</name></author><author><name sortKey="Chatterjee, D" uniqKey="Chatterjee D">D Chatterjee</name></author><author><name sortKey="Chin, Ye" uniqKey="Chin Y">YE Chin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yang, J" uniqKey="Yang J">J Yang</name></author><author><name sortKey="Huang, J" uniqKey="Huang J">J Huang</name></author><author><name sortKey="Dasgupta, M" uniqKey="Dasgupta M">M Dasgupta</name></author><author><name sortKey="Sears, N" uniqKey="Sears N">N Sears</name></author><author><name sortKey="Miyagi, M" uniqKey="Miyagi M">M Miyagi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kumar, V" uniqKey="Kumar V">V Kumar</name></author><author><name sortKey="Cheng, P" uniqKey="Cheng P">P Cheng</name></author><author><name sortKey="Condamine, T" uniqKey="Condamine T">T Condamine</name></author><author><name sortKey="Mony, S" uniqKey="Mony S">S Mony</name></author><author><name sortKey="Languino, Lr" uniqKey="Languino L">LR Languino</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Veeriah, S" uniqKey="Veeriah S">S Veeriah</name></author><author><name sortKey="Brennan, C" uniqKey="Brennan C">C Brennan</name></author><author><name sortKey="Meng, S" uniqKey="Meng S">S Meng</name></author><author><name sortKey="Singh, B" uniqKey="Singh B">B Singh</name></author><author><name sortKey="Fagin, Ja" uniqKey="Fagin J">JA Fagin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhang, X" uniqKey="Zhang X">X Zhang</name></author><author><name sortKey="Guo, A" uniqKey="Guo A">A Guo</name></author><author><name sortKey="Yu, J" uniqKey="Yu J">J Yu</name></author><author><name sortKey="Possemato, A" uniqKey="Possemato A">A Possemato</name></author><author><name sortKey="Chen, Y" uniqKey="Chen Y">Y Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lu, D" uniqKey="Lu D">D Lu</name></author><author><name sortKey="Liu, L" uniqKey="Liu L">L Liu</name></author><author><name sortKey="Ji, X" uniqKey="Ji X">X Ji</name></author><author><name sortKey="Gao, Y" uniqKey="Gao Y">Y Gao</name></author><author><name sortKey="Chen, X" uniqKey="Chen X">X Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nicholson, Se" uniqKey="Nicholson S">SE Nicholson</name></author><author><name sortKey="De Souza, D" uniqKey="De Souza D">D De Souza</name></author><author><name sortKey="Fabri, Lj" uniqKey="Fabri L">LJ Fabri</name></author><author><name sortKey="Corbin, J" uniqKey="Corbin J">J Corbin</name></author><author><name sortKey="Willson, Ta" uniqKey="Willson T">TA Willson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sasaki, A" uniqKey="Sasaki A">A Sasaki</name></author><author><name sortKey="Yasukawa, H" uniqKey="Yasukawa H">H Yasukawa</name></author><author><name sortKey="Suzuki, A" uniqKey="Suzuki A">A Suzuki</name></author><author><name sortKey="Kamizono, S" uniqKey="Kamizono S">S Kamizono</name></author><author><name sortKey="Syoda, T" uniqKey="Syoda T">T Syoda</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chung, Cd" uniqKey="Chung C">CD Chung</name></author><author><name sortKey="Liao, J" uniqKey="Liao J">J Liao</name></author><author><name sortKey="Liu, B" uniqKey="Liu B">B Liu</name></author><author><name sortKey="Rao, X" uniqKey="Rao X">X Rao</name></author><author><name sortKey="Jay, P" uniqKey="Jay P">P Jay</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="King, Ca" uniqKey="King C">CA King</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, Y" uniqKey="Wang Y">Y Wang</name></author><author><name sortKey="Lu, Y" uniqKey="Lu Y">Y Lu</name></author><author><name sortKey="Toh, St" uniqKey="Toh S">ST Toh</name></author><author><name sortKey="Sung, Wk" uniqKey="Sung W">WK Sung</name></author><author><name sortKey="Tan, P" uniqKey="Tan P">P Tan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liao, Xh" uniqKey="Liao X">XH Liao</name></author><author><name sortKey="Xiang, Y" uniqKey="Xiang Y">Y Xiang</name></author><author><name sortKey="Yu, Cx" uniqKey="Yu C">CX Yu</name></author><author><name sortKey="Li, Jp" uniqKey="Li J">JP Li</name></author><author><name sortKey="Li, H" uniqKey="Li H">H Li</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Qin, L" uniqKey="Qin L">L Qin</name></author><author><name sortKey="Li, R" uniqKey="Li R">R Li</name></author><author><name sortKey="Zhang, J" uniqKey="Zhang J">J Zhang</name></author><author><name sortKey="Li, A" uniqKey="Li A">A Li</name></author><author><name sortKey="Luo, R" uniqKey="Luo R">R Luo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cheng, Y" uniqKey="Cheng Y">Y Cheng</name></author><author><name sortKey="Li, Y" uniqKey="Li Y">Y Li</name></author><author><name sortKey="Nian, Y" uniqKey="Nian Y">Y Nian</name></author><author><name sortKey="Liu, D" uniqKey="Liu D">D Liu</name></author><author><name sortKey="Dai, F" uniqKey="Dai F">F Dai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hong, L" uniqKey="Hong L">L Hong</name></author><author><name sortKey="Ya Wei, L" uniqKey="Ya Wei L">L Ya-Wei</name></author><author><name sortKey="Hai, W" uniqKey="Hai W">W Hai</name></author><author><name sortKey="Qiang, Z" uniqKey="Qiang Z">Z Qiang</name></author><author><name sortKey="Jun Jie, L" uniqKey="Jun Jie L">L Jun-Jie</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Patel, K" uniqKey="Patel K">K Patel</name></author><author><name sortKey="Kollory, A" uniqKey="Kollory A">A Kollory</name></author><author><name sortKey="Takashima, A" uniqKey="Takashima A">A Takashima</name></author><author><name sortKey="Sarkar, S" uniqKey="Sarkar S">S Sarkar</name></author><author><name sortKey="Faller, Dv" uniqKey="Faller D">DV Faller</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hatziapostolou, M" uniqKey="Hatziapostolou M">M Hatziapostolou</name></author><author><name sortKey="Polytarchou, C" uniqKey="Polytarchou C">C Polytarchou</name></author><author><name sortKey="Aggelidou, E" uniqKey="Aggelidou E">E Aggelidou</name></author><author><name sortKey="Drakaki, A" uniqKey="Drakaki A">A Drakaki</name></author><author><name sortKey="Poultsides, Ga" uniqKey="Poultsides G">GA Poultsides</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Renne, N" uniqKey="Van Renne N">N Van Renne</name></author><author><name sortKey="Roca Suarez, Aa" uniqKey="Roca Suarez A">AA Roca Suarez</name></author><author><name sortKey="Duong, Fh" uniqKey="Duong F">FH Duong</name></author><author><name sortKey="Gondeau, C" uniqKey="Gondeau C">C Gondeau</name></author><author><name sortKey="Calabrese, D" uniqKey="Calabrese D">D Calabrese</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Devhare, Pb" uniqKey="Devhare P">PB Devhare</name></author><author><name sortKey="Sasaki, R" uniqKey="Sasaki R">R Sasaki</name></author><author><name sortKey="Shrivastava, S" uniqKey="Shrivastava S">S Shrivastava</name></author><author><name sortKey="Di Bisceglie, Am" uniqKey="Di Bisceglie A">AM Di Bisceglie</name></author><author><name sortKey="Ray, R" uniqKey="Ray R">R Ray</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yang, J" uniqKey="Yang J">J Yang</name></author><author><name sortKey="Chatterjee Kishore, M" uniqKey="Chatterjee Kishore M">M Chatterjee-Kishore</name></author><author><name sortKey="Staugaitis, Sm" uniqKey="Staugaitis S">SM Staugaitis</name></author><author><name sortKey="Nguyen, H" uniqKey="Nguyen H">H Nguyen</name></author><author><name sortKey="Schlessinger, K" uniqKey="Schlessinger K">K Schlessinger</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yang, J" uniqKey="Yang J">J Yang</name></author><author><name sortKey="Liao, X" uniqKey="Liao X">X Liao</name></author><author><name sortKey="Agarwal, Mk" uniqKey="Agarwal M">MK Agarwal</name></author><author><name sortKey="Barnes, L" uniqKey="Barnes L">L Barnes</name></author><author><name sortKey="Auron, Pe" uniqKey="Auron P">PE Auron</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ng, Dc" uniqKey="Ng D">DC Ng</name></author><author><name sortKey="Lin, Bh" uniqKey="Lin B">BH Lin</name></author><author><name sortKey="Lim, Cp" uniqKey="Lim C">CP Lim</name></author><author><name sortKey="Huang, G" uniqKey="Huang G">G Huang</name></author><author><name sortKey="Zhang, T" uniqKey="Zhang T">T Zhang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sehgal, Pb" uniqKey="Sehgal P">PB Sehgal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liu, F" uniqKey="Liu F">F Liu</name></author><author><name sortKey="Poursine Laurent, J" uniqKey="Poursine Laurent J">J Poursine-Laurent</name></author><author><name sortKey="Wu, Hy" uniqKey="Wu H">HY Wu</name></author><author><name sortKey="Link, Dc" uniqKey="Link D">DC Link</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hurst, Sm" uniqKey="Hurst S">SM Hurst</name></author><author><name sortKey="Wilkinson, Ts" uniqKey="Wilkinson T">TS Wilkinson</name></author><author><name sortKey="Mcloughlin, Rm" uniqKey="Mcloughlin R">RM McLoughlin</name></author><author><name sortKey="Jones, S" uniqKey="Jones S">S Jones</name></author><author><name sortKey="Horiuchi, S" uniqKey="Horiuchi S">S Horiuchi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mcloughlin, Rm" uniqKey="Mcloughlin R">RM McLoughlin</name></author><author><name sortKey="Jenkins, Bj" uniqKey="Jenkins B">BJ Jenkins</name></author><author><name sortKey="Grail, D" uniqKey="Grail D">D Grail</name></author><author><name sortKey="Williams, As" uniqKey="Williams A">AS Williams</name></author><author><name sortKey="Fielding, Ca" uniqKey="Fielding C">CA Fielding</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Romano, M" uniqKey="Romano M">M Romano</name></author><author><name sortKey="Sironi, M" uniqKey="Sironi M">M Sironi</name></author><author><name sortKey="Toniatti, C" uniqKey="Toniatti C">C Toniatti</name></author><author><name sortKey="Polentarutti, N" uniqKey="Polentarutti N">N Polentarutti</name></author><author><name sortKey="Fruscella, P" uniqKey="Fruscella P">P Fruscella</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chomarat, P" uniqKey="Chomarat P">P Chomarat</name></author><author><name sortKey="Banchereau, J" uniqKey="Banchereau J">J Banchereau</name></author><author><name sortKey="Davoust, J" uniqKey="Davoust J">J Davoust</name></author><author><name sortKey="Palucka, Ak" uniqKey="Palucka A">AK Palucka</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rochman, I" uniqKey="Rochman I">I Rochman</name></author><author><name sortKey="Paul, We" uniqKey="Paul W">WE Paul</name></author><author><name sortKey="Ben Sasson, Sz" uniqKey="Ben Sasson S">SZ Ben-Sasson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yu, Cr" uniqKey="Yu C">CR Yu</name></author><author><name sortKey="Dambuza, Im" uniqKey="Dambuza I">IM Dambuza</name></author><author><name sortKey="Lee, Yj" uniqKey="Lee Y">YJ Lee</name></author><author><name sortKey="Frank, Gm" uniqKey="Frank G">GM Frank</name></author><author><name sortKey="Egwuagu, Ce" uniqKey="Egwuagu C">CE Egwuagu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ivanov, Ii" uniqKey="Ivanov I">II Ivanov</name></author><author><name sortKey="Mckenzie, Bs" uniqKey="Mckenzie B">BS McKenzie</name></author><author><name sortKey="Zhou, L" uniqKey="Zhou L">L Zhou</name></author><author><name sortKey="Tadokoro, Ce" uniqKey="Tadokoro C">CE Tadokoro</name></author><author><name sortKey="Lepelley, A" uniqKey="Lepelley A">A Lepelley</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nowell, Ma" uniqKey="Nowell M">MA Nowell</name></author><author><name sortKey="Williams, As" uniqKey="Williams A">AS Williams</name></author><author><name sortKey="Carty, Sa" uniqKey="Carty S">SA Carty</name></author><author><name sortKey="Scheller, J" uniqKey="Scheller J">J Scheller</name></author><author><name sortKey="Hayes, Aj" uniqKey="Hayes A">AJ Hayes</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Korn, T" uniqKey="Korn T">T Korn</name></author><author><name sortKey="Mitsdoerffer, M" uniqKey="Mitsdoerffer M">M Mitsdoerffer</name></author><author><name sortKey="Croxford, Al" uniqKey="Croxford A">AL Croxford</name></author><author><name sortKey="Awasthi, A" uniqKey="Awasthi A">A Awasthi</name></author><author><name sortKey="Dardalhon, Va" uniqKey="Dardalhon V">VA Dardalhon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Eto, D" uniqKey="Eto D">D Eto</name></author><author><name sortKey="Lao, C" uniqKey="Lao C">C Lao</name></author><author><name sortKey="Ditoro, D" uniqKey="Ditoro D">D DiToro</name></author><author><name sortKey="Barnett, B" uniqKey="Barnett B">B Barnett</name></author><author><name sortKey="Escobar, Tc" uniqKey="Escobar T">TC Escobar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ma, Cs" uniqKey="Ma C">CS Ma</name></author><author><name sortKey="Avery, Dt" uniqKey="Avery D">DT Avery</name></author><author><name sortKey="Chan, A" uniqKey="Chan A">A Chan</name></author><author><name sortKey="Batten, M" uniqKey="Batten M">M Batten</name></author><author><name sortKey="Bustamante, J" uniqKey="Bustamante J">J Bustamante</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ma, Cs" uniqKey="Ma C">CS Ma</name></author><author><name sortKey="Deenick, Ek" uniqKey="Deenick E">EK Deenick</name></author><author><name sortKey="Batten, M" uniqKey="Batten M">M Batten</name></author><author><name sortKey="Tangye, Sg" uniqKey="Tangye S">SG Tangye</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ouyang, W" uniqKey="Ouyang W">W Ouyang</name></author><author><name sortKey="Rutz, S" uniqKey="Rutz S">S Rutz</name></author><author><name sortKey="Crellin, Nk" uniqKey="Crellin N">NK Crellin</name></author><author><name sortKey="Valdez, Pa" uniqKey="Valdez P">PA Valdez</name></author><author><name sortKey="Hymowitz, Sg" uniqKey="Hymowitz S">SG Hymowitz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wu, C" uniqKey="Wu C">C Wu</name></author><author><name sortKey="Orozco, C" uniqKey="Orozco C">C Orozco</name></author><author><name sortKey="Boyer, J" uniqKey="Boyer J">J Boyer</name></author><author><name sortKey="Leglise, M" uniqKey="Leglise M">M Leglise</name></author><author><name sortKey="Goodale, J" uniqKey="Goodale J">J Goodale</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yasukawa, H" uniqKey="Yasukawa H">H Yasukawa</name></author><author><name sortKey="Ohishi, M" uniqKey="Ohishi M">M Ohishi</name></author><author><name sortKey="Mori, H" uniqKey="Mori H">H Mori</name></author><author><name sortKey="Murakami, M" uniqKey="Murakami M">M Murakami</name></author><author><name sortKey="Chinen, T" uniqKey="Chinen T">T Chinen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yoshimura, A" uniqKey="Yoshimura A">A Yoshimura</name></author><author><name sortKey="Naka, T" uniqKey="Naka T">T Naka</name></author><author><name sortKey="Kubo, M" uniqKey="Kubo M">M Kubo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cavani, A" uniqKey="Cavani A">A Cavani</name></author><author><name sortKey="Nasorri, F" uniqKey="Nasorri F">F Nasorri</name></author><author><name sortKey="Prezzi, C" uniqKey="Prezzi C">C Prezzi</name></author><author><name sortKey="Sebastiani, S" uniqKey="Sebastiani S">S Sebastiani</name></author><author><name sortKey="Albanesi, C" uniqKey="Albanesi C">C Albanesi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Itoh, K" uniqKey="Itoh K">K Itoh</name></author><author><name sortKey="Hirohata, S" uniqKey="Hirohata S">S Hirohata</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Saito, M" uniqKey="Saito M">M Saito</name></author><author><name sortKey="Nagasawa, M" uniqKey="Nagasawa M">M Nagasawa</name></author><author><name sortKey="Takada, H" uniqKey="Takada H">H Takada</name></author><author><name sortKey="Hara, T" uniqKey="Hara T">T Hara</name></author><author><name sortKey="Tsuchiya, S" uniqKey="Tsuchiya S">S Tsuchiya</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Raftery, N" uniqKey="Raftery N">N Raftery</name></author><author><name sortKey="Stevenson, Nj" uniqKey="Stevenson N">NJ Stevenson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Darnell, Je" uniqKey="Darnell J">JE Darnell</name></author><author><name sortKey="Kerr, Im" uniqKey="Kerr I">IM Kerr</name></author><author><name sortKey="Stark, Gr" uniqKey="Stark G">GR Stark</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Velichko, S" uniqKey="Velichko S">S Velichko</name></author><author><name sortKey="Wagner, Tc" uniqKey="Wagner T">TC Wagner</name></author><author><name sortKey="Turkson, J" uniqKey="Turkson J">J Turkson</name></author><author><name sortKey="Jove, R" uniqKey="Jove R">R Jove</name></author><author><name sortKey="Croze, E" uniqKey="Croze E">E Croze</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, Wb" uniqKey="Wang W">WB Wang</name></author><author><name sortKey="Levy, De" uniqKey="Levy D">DE Levy</name></author><author><name sortKey="Lee, Ck" uniqKey="Lee C">CK Lee</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ho, Hh" uniqKey="Ho H">HH Ho</name></author><author><name sortKey="Ivashkiv, Lb" uniqKey="Ivashkiv L">LB Ivashkiv</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lupberger, J" uniqKey="Lupberger J">J Lupberger</name></author><author><name sortKey="Duong, Fh" uniqKey="Duong F">FH Duong</name></author><author><name sortKey="Fofana, I" uniqKey="Fofana I">I Fofana</name></author><author><name sortKey="Zona, L" uniqKey="Zona L">L Zona</name></author><author><name sortKey="Xiao, F" uniqKey="Xiao F">F Xiao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Icardi, L" uniqKey="Icardi L">L Icardi</name></author><author><name sortKey="Mori, R" uniqKey="Mori R">R Mori</name></author><author><name sortKey="Gesellchen, V" uniqKey="Gesellchen V">V Gesellchen</name></author><author><name sortKey="Eyckerman, S" uniqKey="Eyckerman S">S Eyckerman</name></author><author><name sortKey="De Cauwer, L" uniqKey="De Cauwer L">L De Cauwer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ivashkiv, Lb" uniqKey="Ivashkiv L">LB Ivashkiv</name></author><author><name sortKey="Donlin, Lt" uniqKey="Donlin L">LT Donlin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Heim, Mh" uniqKey="Heim M">MH Heim</name></author><author><name sortKey="Jean Francois Dufour, P Ac" uniqKey="Jean Francois Dufour P">P-AC Jean-François Dufour</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Karin, M" uniqKey="Karin M">M Karin</name></author><author><name sortKey="Clevers, H" uniqKey="Clevers H">H Clevers</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Michalopoulos, Gk" uniqKey="Michalopoulos G">GK Michalopoulos</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Michalopoulos, Gk" uniqKey="Michalopoulos G">GK Michalopoulos</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Robinson, Mw" uniqKey="Robinson M">MW Robinson</name></author><author><name sortKey="Harmon, C" uniqKey="Harmon C">C Harmon</name></author><author><name sortKey="O Farrelly, C" uniqKey="O Farrelly C">C O'Farrelly</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Selzner, N" uniqKey="Selzner N">N Selzner</name></author><author><name sortKey="Selzner, M" uniqKey="Selzner M">M Selzner</name></author><author><name sortKey="Odermatt, B" uniqKey="Odermatt B">B Odermatt</name></author><author><name sortKey="Tian, Y" uniqKey="Tian Y">Y Tian</name></author><author><name sortKey="Van Rooijen, N" uniqKey="Van Rooijen N">N Van Rooijen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Michalopoulos, Gk" uniqKey="Michalopoulos G">GK Michalopoulos</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yu, H" uniqKey="Yu H">H Yu</name></author><author><name sortKey="Lee, H" uniqKey="Lee H">H Lee</name></author><author><name sortKey="Herrmann, A" uniqKey="Herrmann A">A Herrmann</name></author><author><name sortKey="Buettner, R" uniqKey="Buettner R">R Buettner</name></author><author><name sortKey="Jove, R" uniqKey="Jove R">R Jove</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Holland, Sm" uniqKey="Holland S">SM Holland</name></author><author><name sortKey="Deleo, Fr" uniqKey="Deleo F">FR DeLeo</name></author><author><name sortKey="Elloumi, Hz" uniqKey="Elloumi H">HZ Elloumi</name></author><author><name sortKey="Hsu, Ap" uniqKey="Hsu A">AP Hsu</name></author><author><name sortKey="Uzel, G" uniqKey="Uzel G">G Uzel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Siegel, Am" uniqKey="Siegel A">AM Siegel</name></author><author><name sortKey="Heimall, J" uniqKey="Heimall J">J Heimall</name></author><author><name sortKey="Freeman, Af" uniqKey="Freeman A">AF Freeman</name></author><author><name sortKey="Hsu, Ap" uniqKey="Hsu A">AP Hsu</name></author><author><name sortKey="Brittain, E" uniqKey="Brittain E">E Brittain</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Waris, G" uniqKey="Waris G">G Waris</name></author><author><name sortKey="Siddiqui, A" uniqKey="Siddiqui A">A Siddiqui</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lee, Yh" uniqKey="Lee Y">YH Lee</name></author><author><name sortKey="Yun, Y" uniqKey="Yun Y">Y Yun</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yuan, K" uniqKey="Yuan K">K Yuan</name></author><author><name sortKey="Lei, Y" uniqKey="Lei Y">Y Lei</name></author><author><name sortKey="Chen, Hn" uniqKey="Chen H">HN Chen</name></author><author><name sortKey="Chen, Y" uniqKey="Chen Y">Y Chen</name></author><author><name sortKey="Zhang, T" uniqKey="Zhang T">T Zhang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mccartney, Em" uniqKey="Mccartney E">EM McCartney</name></author><author><name sortKey="Helbig, Kj" uniqKey="Helbig K">KJ Helbig</name></author><author><name sortKey="Narayana, Sk" uniqKey="Narayana S">SK Narayana</name></author><author><name sortKey="Eyre, Ns" uniqKey="Eyre N">NS Eyre</name></author><author><name sortKey="Aloia, Al" uniqKey="Aloia A">AL Aloia</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yoshida, T" uniqKey="Yoshida T">T Yoshida</name></author><author><name sortKey="Hanada, T" uniqKey="Hanada T">T Hanada</name></author><author><name sortKey="Tokuhisa, T" uniqKey="Tokuhisa T">T Tokuhisa</name></author><author><name sortKey="Kosai, K" uniqKey="Kosai K">K Kosai</name></author><author><name sortKey="Sata, M" uniqKey="Sata M">M Sata</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gong, G" uniqKey="Gong G">G Gong</name></author><author><name sortKey="Waris, G" uniqKey="Waris G">G Waris</name></author><author><name sortKey="Tanveer, R" uniqKey="Tanveer R">R Tanveer</name></author><author><name sortKey="Siddiqui, A" uniqKey="Siddiqui A">A Siddiqui</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pinkham, C" uniqKey="Pinkham C">C Pinkham</name></author><author><name sortKey="An, S" uniqKey="An S">S An</name></author><author><name sortKey="Lundberg, L" uniqKey="Lundberg L">L Lundberg</name></author><author><name sortKey="Bansal, N" uniqKey="Bansal N">N Bansal</name></author><author><name sortKey="Benedict, A" uniqKey="Benedict A">A Benedict</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Slinger, E" uniqKey="Slinger E">E Slinger</name></author><author><name sortKey="Maussang, D" uniqKey="Maussang D">D Maussang</name></author><author><name sortKey="Schreiber, A" uniqKey="Schreiber A">A Schreiber</name></author><author><name sortKey="Siderius, M" uniqKey="Siderius M">M Siderius</name></author><author><name sortKey="Rahbar, A" uniqKey="Rahbar A">A Rahbar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lepiller, Q" uniqKey="Lepiller Q">Q Lepiller</name></author><author><name sortKey="Abbas, W" uniqKey="Abbas W">W Abbas</name></author><author><name sortKey="Kumar, A" uniqKey="Kumar A">A Kumar</name></author><author><name sortKey="Tripathy, Mk" uniqKey="Tripathy M">MK Tripathy</name></author><author><name sortKey="Herbein, G" uniqKey="Herbein G">G Herbein</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kotenko, Sv" uniqKey="Kotenko S">SV Kotenko</name></author><author><name sortKey="Saccani, S" uniqKey="Saccani S">S Saccani</name></author><author><name sortKey="Izotova, Ls" uniqKey="Izotova L">LS Izotova</name></author><author><name sortKey="Mirochnitchenko, Ov" uniqKey="Mirochnitchenko O">OV Mirochnitchenko</name></author><author><name sortKey="Pestka, S" uniqKey="Pestka S">S Pestka</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Raftery, Mj" uniqKey="Raftery M">MJ Raftery</name></author><author><name sortKey="Wieland, D" uniqKey="Wieland D">D Wieland</name></author><author><name sortKey="Gronewald, S" uniqKey="Gronewald S">S Gronewald</name></author><author><name sortKey="Kraus, Aa" uniqKey="Kraus A">AA Kraus</name></author><author><name sortKey="Giese, T" uniqKey="Giese T">T Giese</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Spencer, Jv" uniqKey="Spencer J">JV Spencer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, H" uniqKey="Chen H">H Chen</name></author><author><name sortKey="Hutt Fletcher, L" uniqKey="Hutt Fletcher L">L Hutt-Fletcher</name></author><author><name sortKey="Cao, L" uniqKey="Cao L">L Cao</name></author><author><name sortKey="Hayward, Sd" uniqKey="Hayward S">SD Hayward</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kung, Cp" uniqKey="Kung C">CP Kung</name></author><author><name sortKey="Meckes, Dg" uniqKey="Meckes D">DG Meckes</name></author><author><name sortKey="Raab Traub, N" uniqKey="Raab Traub N">N Raab-Traub</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Muromoto, R" uniqKey="Muromoto R">R Muromoto</name></author><author><name sortKey="Ikeda, O" uniqKey="Ikeda O">O Ikeda</name></author><author><name sortKey="Okabe, K" uniqKey="Okabe K">K Okabe</name></author><author><name sortKey="Togi, S" uniqKey="Togi S">S Togi</name></author><author><name sortKey="Kamitani, S" uniqKey="Kamitani S">S Kamitani</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Moore, Kw" uniqKey="Moore K">KW Moore</name></author><author><name sortKey="Vieira, P" uniqKey="Vieira P">P Vieira</name></author><author><name sortKey="Fiorentino, Df" uniqKey="Fiorentino D">DF Fiorentino</name></author><author><name sortKey="Trounstine, Ml" uniqKey="Trounstine M">ML Trounstine</name></author><author><name sortKey="Khan, Ta" uniqKey="Khan T">TA Khan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ding, Y" uniqKey="Ding Y">Y Ding</name></author><author><name sortKey="Qin, L" uniqKey="Qin L">L Qin</name></author><author><name sortKey="Kotenko, Sv" uniqKey="Kotenko S">SV Kotenko</name></author><author><name sortKey="Pestka, S" uniqKey="Pestka S">S Pestka</name></author><author><name sortKey="Bromberg, Js" uniqKey="Bromberg J">JS Bromberg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wan, X" uniqKey="Wan X">X Wan</name></author><author><name sortKey="Wang, H" uniqKey="Wang H">H Wang</name></author><author><name sortKey="Nicholas, J" uniqKey="Nicholas J">J Nicholas</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Santarelli, R" uniqKey="Santarelli R">R Santarelli</name></author><author><name sortKey="Gonnella, R" uniqKey="Gonnella R">R Gonnella</name></author><author><name sortKey="Di Giovenale, G" uniqKey="Di Giovenale G">G Di Giovenale</name></author><author><name sortKey="Cuomo, L" uniqKey="Cuomo L">L Cuomo</name></author><author><name sortKey="Capobianchi, A" uniqKey="Capobianchi A">A Capobianchi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sen, N" uniqKey="Sen N">N Sen</name></author><author><name sortKey="Che, X" uniqKey="Che X">X Che</name></author><author><name sortKey="Rajamani, J" uniqKey="Rajamani J">J Rajamani</name></author><author><name sortKey="Zerboni, L" uniqKey="Zerboni L">L Zerboni</name></author><author><name sortKey="Sung, P" uniqKey="Sung P">P Sung</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Docherty, Jj" uniqKey="Docherty J">JJ Docherty</name></author><author><name sortKey="Sweet, Tj" uniqKey="Sweet T">TJ Sweet</name></author><author><name sortKey="Bailey, E" uniqKey="Bailey E">E Bailey</name></author><author><name sortKey="Faith, Sa" uniqKey="Faith S">SA Faith</name></author><author><name sortKey="Booth, T" uniqKey="Booth T">T Booth</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhu, S" uniqKey="Zhu S">S Zhu</name></author><author><name sortKey="Luo, H" uniqKey="Luo H">H Luo</name></author><author><name sortKey="Liu, H" uniqKey="Liu H">H Liu</name></author><author><name sortKey="Ha, Y" uniqKey="Ha Y">Y Ha</name></author><author><name sortKey="Mays, Er" uniqKey="Mays E">ER Mays</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Aid, M" uniqKey="Aid M">M Aid</name></author><author><name sortKey="Abbink, P" uniqKey="Abbink P">P Abbink</name></author><author><name sortKey="Larocca, Ra" uniqKey="Larocca R">RA Larocca</name></author><author><name sortKey="Boyd, M" uniqKey="Boyd M">M Boyd</name></author><author><name sortKey="Nityanandam, R" uniqKey="Nityanandam R">R Nityanandam</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ulane, Cm" uniqKey="Ulane C">CM Ulane</name></author><author><name sortKey="Rodriguez, Jj" uniqKey="Rodriguez J">JJ Rodriguez</name></author><author><name sortKey="Parisien, Jp" uniqKey="Parisien J">JP Parisien</name></author><author><name sortKey="Horvath, Cm" uniqKey="Horvath C">CM Horvath</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Palosaari, H" uniqKey="Palosaari H">H Palosaari</name></author><author><name sortKey="Parisien, Jp" uniqKey="Parisien J">JP Parisien</name></author><author><name sortKey="Rodriguez, Jj" uniqKey="Rodriguez J">JJ Rodriguez</name></author><author><name sortKey="Ulane, Cm" uniqKey="Ulane C">CM Ulane</name></author><author><name sortKey="Horvath, Cm" uniqKey="Horvath C">CM Horvath</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hui, Kp" uniqKey="Hui K">KP Hui</name></author><author><name sortKey="Li, Hs" uniqKey="Li H">HS Li</name></author><author><name sortKey="Cheung, Mc" uniqKey="Cheung M">MC Cheung</name></author><author><name sortKey="Chan, Rw" uniqKey="Chan R">RW Chan</name></author><author><name sortKey="Yuen, Km" uniqKey="Yuen K">KM Yuen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jia, D" uniqKey="Jia D">D Jia</name></author><author><name sortKey="Rahbar, R" uniqKey="Rahbar R">R Rahbar</name></author><author><name sortKey="Chan, Rw" uniqKey="Chan R">RW Chan</name></author><author><name sortKey="Lee, Sm" uniqKey="Lee S">SM Lee</name></author><author><name sortKey="Chan, Mc" uniqKey="Chan M">MC Chan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chandra, V" uniqKey="Chandra V">V Chandra</name></author><author><name sortKey="Kar Roy, A" uniqKey="Kar Roy A">A Kar-Roy</name></author><author><name sortKey="Kumari, S" uniqKey="Kumari S">S Kumari</name></author><author><name sortKey="Mayor, S" uniqKey="Mayor S">S Mayor</name></author><author><name sortKey="Jameel, S" uniqKey="Jameel S">S Jameel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lieu, Kg" uniqKey="Lieu K">KG Lieu</name></author><author><name sortKey="Brice, A" uniqKey="Brice A">A Brice</name></author><author><name sortKey="Wiltzer, L" uniqKey="Wiltzer L">L Wiltzer</name></author><author><name sortKey="Hirst, B" uniqKey="Hirst B">B Hirst</name></author><author><name sortKey="Jans, Da" uniqKey="Jans D">DA Jans</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mitzel, Dn" uniqKey="Mitzel D">DN Mitzel</name></author><author><name sortKey="Jaramillo, Rj" uniqKey="Jaramillo R">RJ Jaramillo</name></author><author><name sortKey="Stout Delgado, H" uniqKey="Stout Delgado H">H Stout-Delgado</name></author><author><name sortKey="Senft, Ap" uniqKey="Senft A">AP Senft</name></author><author><name sortKey="Harrod, Ks" uniqKey="Harrod K">KS Harrod</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Reitsma, Jm" uniqKey="Reitsma J">JM Reitsma</name></author><author><name sortKey="Sato, H" uniqKey="Sato H">H Sato</name></author><author><name sortKey="Nevels, M" uniqKey="Nevels M">M Nevels</name></author><author><name sortKey="Terhune, Ss" uniqKey="Terhune S">SS Terhune</name></author><author><name sortKey="Paulus, C" uniqKey="Paulus C">C Paulus</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ramalingam, D" uniqKey="Ramalingam D">D Ramalingam</name></author><author><name sortKey="Ziegelbauer, Jm" uniqKey="Ziegelbauer J">JM Ziegelbauer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Li, L" uniqKey="Li L">L Li</name></author><author><name sortKey="Chong, Hc" uniqKey="Chong H">HC Chong</name></author><author><name sortKey="Ng, Sy" uniqKey="Ng S">SY Ng</name></author><author><name sortKey="Kwok, Kw" uniqKey="Kwok K">KW Kwok</name></author><author><name sortKey="Teo, Z" uniqKey="Teo Z">Z Teo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kane, M" uniqKey="Kane M">M Kane</name></author><author><name sortKey="Golovkina, T" uniqKey="Golovkina T">T Golovkina</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Danthi, P" uniqKey="Danthi P">P Danthi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yu, H" uniqKey="Yu H">H Yu</name></author><author><name sortKey="Kortylewski, M" uniqKey="Kortylewski M">M Kortylewski</name></author><author><name sortKey="Pardoll, D" uniqKey="Pardoll D">D Pardoll</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Koganti, S" uniqKey="Koganti S">S Koganti</name></author><author><name sortKey="Clark, C" uniqKey="Clark C">C Clark</name></author><author><name sortKey="Zhi, J" uniqKey="Zhi J">J Zhi</name></author><author><name sortKey="Li, X" uniqKey="Li X">X Li</name></author><author><name sortKey="Chen, Ei" uniqKey="Chen E">EI Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="King, Ca" uniqKey="King C">CA King</name></author><author><name sortKey="Li, X" uniqKey="Li X">X Li</name></author><author><name sortKey="Barbachano Guerrero, A" uniqKey="Barbachano Guerrero A">A Barbachano-Guerrero</name></author><author><name sortKey="Bhaduri Mcintosh, S" uniqKey="Bhaduri Mcintosh S">S Bhaduri-McIntosh</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhang, D" uniqKey="Zhang D">D Zhang</name></author><author><name sortKey="Sun, M" uniqKey="Sun M">M Sun</name></author><author><name sortKey="Samols, D" uniqKey="Samols D">D Samols</name></author><author><name sortKey="Kushner, I" uniqKey="Kushner I">I Kushner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lv, D" uniqKey="Lv D">D Lv</name></author><author><name sortKey="Zhang, Y" uniqKey="Zhang Y">Y Zhang</name></author><author><name sortKey="Kim, Hj" uniqKey="Kim H">HJ Kim</name></author><author><name sortKey="Zhang, L" uniqKey="Zhang L">L Zhang</name></author><author><name sortKey="Ma, X" uniqKey="Ma X">X Ma</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Halary, F" uniqKey="Halary F">F Halary</name></author><author><name sortKey="Amara, A" uniqKey="Amara A">A Amara</name></author><author><name sortKey="Lortat Jacob, H" uniqKey="Lortat Jacob H">H Lortat-Jacob</name></author><author><name sortKey="Messerle, M" uniqKey="Messerle M">M Messerle</name></author><author><name sortKey="Delaunay, T" uniqKey="Delaunay T">T Delaunay</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shin, Ec" uniqKey="Shin E">EC Shin</name></author><author><name sortKey="Sung, Ps" uniqKey="Sung P">PS Sung</name></author><author><name sortKey="Park, Sh" uniqKey="Park S">SH Park</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ren, Jp" uniqKey="Ren J">JP Ren</name></author><author><name sortKey="Wang, L" uniqKey="Wang L">L Wang</name></author><author><name sortKey="Zhao, J" uniqKey="Zhao J">J Zhao</name></author><author><name sortKey="Ning, Sb" uniqKey="Ning S">SB Ning</name></author><author><name sortKey="El Gazzar, M" uniqKey="El Gazzar M">M El Gazzar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhai, N" uniqKey="Zhai N">N Zhai</name></author><author><name sortKey="Li, H" uniqKey="Li H">H Li</name></author><author><name sortKey="Song, H" uniqKey="Song H">H Song</name></author><author><name sortKey="Yang, Y" uniqKey="Yang Y">Y Yang</name></author><author><name sortKey="Cui, A" uniqKey="Cui A">A Cui</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wan, S" uniqKey="Wan S">S Wan</name></author><author><name sortKey="Kuo, N" uniqKey="Kuo N">N Kuo</name></author><author><name sortKey="Kryczek, I" uniqKey="Kryczek I">I Kryczek</name></author><author><name sortKey="Zou, W" uniqKey="Zou W">W Zou</name></author><author><name sortKey="Welling, Th" uniqKey="Welling T">TH Welling</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wolk, B" uniqKey="Wolk B">B Wolk</name></author><author><name sortKey="Buchele, B" uniqKey="Buchele B">B Buchele</name></author><author><name sortKey="Moradpour, D" uniqKey="Moradpour D">D Moradpour</name></author><author><name sortKey="Rice, Cm" uniqKey="Rice C">CM Rice</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Roohvand, F" uniqKey="Roohvand F">F Roohvand</name></author><author><name sortKey="Maillard, P" uniqKey="Maillard P">P Maillard</name></author><author><name sortKey="Lavergne, Jp" uniqKey="Lavergne J">JP Lavergne</name></author><author><name sortKey="Boulant, S" uniqKey="Boulant S">S Boulant</name></author><author><name sortKey="Walic, M" uniqKey="Walic M">M Walic</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Llovet, Jm" uniqKey="Llovet J">JM Llovet</name></author><author><name sortKey="Zucman Rossi, J" uniqKey="Zucman Rossi J">J Zucman-Rossi</name></author><author><name sortKey="Pikarsky, E" uniqKey="Pikarsky E">E Pikarsky</name></author><author><name sortKey="Sangro, B" uniqKey="Sangro B">B Sangro</name></author><author><name sortKey="Schwartz, M" uniqKey="Schwartz M">M Schwartz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ho, Y" uniqKey="Ho Y">Y Ho</name></author><author><name sortKey="Tsao, Sw" uniqKey="Tsao S">SW Tsao</name></author><author><name sortKey="Zeng, M" uniqKey="Zeng M">M Zeng</name></author><author><name sortKey="Lui, Vw" uniqKey="Lui V">VW Lui</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lui, Vw" uniqKey="Lui V">VW Lui</name></author><author><name sortKey="Wong, Ey" uniqKey="Wong E">EY Wong</name></author><author><name sortKey="Ho, Y" uniqKey="Ho Y">Y Ho</name></author><author><name sortKey="Hong, B" uniqKey="Hong B">B Hong</name></author><author><name sortKey="Wong, Sc" uniqKey="Wong S">SC Wong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kondo, S" uniqKey="Kondo S">S Kondo</name></author><author><name sortKey="Yoshizaki, T" uniqKey="Yoshizaki T">T Yoshizaki</name></author><author><name sortKey="Wakisaka, N" uniqKey="Wakisaka N">N Wakisaka</name></author><author><name sortKey="Horikawa, T" uniqKey="Horikawa T">T Horikawa</name></author><author><name sortKey="Murono, S" uniqKey="Murono S">S Murono</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wong, Ala" uniqKey="Wong A">ALA Wong</name></author><author><name sortKey="Hirpara, Jl" uniqKey="Hirpara J">JL Hirpara</name></author><author><name sortKey="Pervaiz, S" uniqKey="Pervaiz S">S Pervaiz</name></author><author><name sortKey="Eu, Jq" uniqKey="Eu J">JQ Eu</name></author><author><name sortKey="Sethi, G" uniqKey="Sethi G">G Sethi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Niu, Y" uniqKey="Niu Y">Y Niu</name></author><author><name sortKey="Si, Y" uniqKey="Si Y">Y Si</name></author><author><name sortKey="Li, Y" uniqKey="Li Y">Y Li</name></author><author><name sortKey="Chi, X" uniqKey="Chi X">X Chi</name></author><author><name sortKey="Li, X" uniqKey="Li X">X Li</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yang, Y" uniqKey="Yang Y">Y Yang</name></author><author><name sortKey="Zheng, B" uniqKey="Zheng B">B Zheng</name></author><author><name sortKey="Han, Q" uniqKey="Han Q">Q Han</name></author><author><name sortKey="Zhang, C" uniqKey="Zhang C">C Zhang</name></author><author><name sortKey="Tian, Z" uniqKey="Tian Z">Z Tian</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Miklossy, G" uniqKey="Miklossy G">G Miklossy</name></author><author><name sortKey="Hilliard, Ts" uniqKey="Hilliard T">TS Hilliard</name></author><author><name sortKey="Turkson, J" uniqKey="Turkson J">J Turkson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Espinoza, Jl" uniqKey="Espinoza J">JL Espinoza</name></author><author><name sortKey="Takami, A" uniqKey="Takami A">A Takami</name></author><author><name sortKey="Trung, Lq" uniqKey="Trung L">LQ Trung</name></author><author><name sortKey="Kato, S" uniqKey="Kato S">S Kato</name></author><author><name sortKey="Nakao, S" uniqKey="Nakao S">S Nakao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="De Leo, A" uniqKey="De Leo A">A De Leo</name></author><author><name sortKey="Arena, G" uniqKey="Arena G">G Arena</name></author><author><name sortKey="Lacanna, E" uniqKey="Lacanna E">E Lacanna</name></author><author><name sortKey="Oliviero, G" uniqKey="Oliviero G">G Oliviero</name></author><author><name sortKey="Colavita, F" uniqKey="Colavita F">F Colavita</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Liu, Cl" uniqKey="Liu C">CL Liu</name></author><author><name sortKey="Hung, Hc" uniqKey="Hung H">HC Hung</name></author><author><name sortKey="Lo, Sc" uniqKey="Lo S">SC Lo</name></author><author><name sortKey="Chiang, Ch" uniqKey="Chiang C">CH Chiang</name></author><author><name sortKey="Chen, Ij" uniqKey="Chen I">IJ Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, K" uniqKey="Kim K">K Kim</name></author><author><name sortKey="Kim, Kh" uniqKey="Kim K">KH Kim</name></author><author><name sortKey="Kim, Hy" uniqKey="Kim H">HY Kim</name></author><author><name sortKey="Cho, Hk" uniqKey="Cho H">HK Cho</name></author><author><name sortKey="Sakamoto, N" uniqKey="Sakamoto N">N Sakamoto</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Michaelis, M" uniqKey="Michaelis M">M Michaelis</name></author><author><name sortKey="Paulus, C" uniqKey="Paulus C">C Paulus</name></author><author><name sortKey="Loschmann, N" uniqKey="Loschmann N">N Loschmann</name></author><author><name sortKey="Dauth, S" uniqKey="Dauth S">S Dauth</name></author><author><name sortKey="Stange, E" uniqKey="Stange E">E Stange</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Furtek, Sl" uniqKey="Furtek S">SL Furtek</name></author><author><name sortKey="Backos, Ds" uniqKey="Backos D">DS Backos</name></author><author><name sortKey="Matheson, Cj" uniqKey="Matheson C">CJ Matheson</name></author><author><name sortKey="Reigan, P" uniqKey="Reigan P">P Reigan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gharwan, H" uniqKey="Gharwan H">H Gharwan</name></author><author><name sortKey="Groninger, H" uniqKey="Groninger H">H Groninger</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Heppler, Ln" uniqKey="Heppler L">LN Heppler</name></author><author><name sortKey="Frank, Da" uniqKey="Frank D">DA Frank</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Baell, J" uniqKey="Baell J">J Baell</name></author><author><name sortKey="Walters, Ma" uniqKey="Walters M">MA Walters</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Hubbard, Jm" uniqKey="Hubbard J">JM Hubbard</name></author><author><name sortKey="Grothey, A" uniqKey="Grothey A">A Grothey</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="review-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Pathog</journal-id><journal-id journal-id-type="iso-abbrev">PLoS Pathog</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plospath</journal-id><journal-title-group><journal-title>PLoS Pathogens</journal-title></journal-title-group><issn pub-type="ppub">1553-7366</issn><issn pub-type="epub">1553-7374</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, CA USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">29543893</article-id><article-id pub-id-type="pmc">5854428</article-id><article-id pub-id-type="doi">10.1371/journal.ppat.1006839</article-id><article-id pub-id-type="publisher-id">PPATHOGENS-D-17-02294</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review</subject></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Proteins</subject><subj-group><subject>Post-Translational Modification</subject><subj-group><subject>Phosphorylation</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Proteins</subject><subj-group><subject>STAT proteins</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Cell biology</subject><subj-group><subject>Signal transduction</subject><subj-group><subject>Cell signaling</subject><subj-group><subject>STAT signaling</subject></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Organisms</subject><subj-group><subject>Viruses</subject><subj-group><subject>RNA viruses</subject><subj-group><subject>Flaviviruses</subject><subj-group><subject>Hepacivirus</subject><subj-group><subject>Hepatitis C virus</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Microbiology</subject><subj-group><subject>Medical microbiology</subject><subj-group><subject>Microbial pathogens</subject><subj-group><subject>Viral pathogens</subject><subj-group><subject>Flaviviruses</subject><subj-group><subject>Hepacivirus</subject><subj-group><subject>Hepatitis C virus</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and health sciences</subject><subj-group><subject>Pathology and laboratory medicine</subject><subj-group><subject>Pathogens</subject><subj-group><subject>Microbial pathogens</subject><subj-group><subject>Viral pathogens</subject><subj-group><subject>Flaviviruses</subject><subj-group><subject>Hepacivirus</subject><subj-group><subject>Hepatitis C virus</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Organisms</subject><subj-group><subject>Viruses</subject><subj-group><subject>Viral pathogens</subject><subj-group><subject>Flaviviruses</subject><subj-group><subject>Hepacivirus</subject><subj-group><subject>Hepatitis C virus</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Microbiology</subject><subj-group><subject>Medical microbiology</subject><subj-group><subject>Microbial pathogens</subject><subj-group><subject>Viral pathogens</subject><subj-group><subject>Hepatitis viruses</subject><subj-group><subject>Hepatitis C virus</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and health sciences</subject><subj-group><subject>Pathology and laboratory medicine</subject><subj-group><subject>Pathogens</subject><subj-group><subject>Microbial pathogens</subject><subj-group><subject>Viral pathogens</subject><subj-group><subject>Hepatitis viruses</subject><subj-group><subject>Hepatitis C virus</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Organisms</subject><subj-group><subject>Viruses</subject><subj-group><subject>Viral pathogens</subject><subj-group><subject>Hepatitis viruses</subject><subj-group><subject>Hepatitis C virus</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Microbiology</subject><subj-group><subject>Medical microbiology</subject><subj-group><subject>Microbial pathogens</subject><subj-group><subject>Viral pathogens</subject><subj-group><subject>Hepatitis viruses</subject><subj-group><subject>Hepatitis B virus</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and health sciences</subject><subj-group><subject>Pathology and laboratory medicine</subject><subj-group><subject>Pathogens</subject><subj-group><subject>Microbial pathogens</subject><subj-group><subject>Viral pathogens</subject><subj-group><subject>Hepatitis viruses</subject><subj-group><subject>Hepatitis B virus</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Organisms</subject><subj-group><subject>Viruses</subject><subj-group><subject>Viral pathogens</subject><subj-group><subject>Hepatitis viruses</subject><subj-group><subject>Hepatitis B virus</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune Response</subject><subj-group><subject>Inflammation</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Immunology</subject><subj-group><subject>Immune Response</subject><subj-group><subject>Inflammation</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Diagnostic Medicine</subject><subj-group><subject>Signs and Symptoms</subject><subj-group><subject>Inflammation</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Pathology and Laboratory Medicine</subject><subj-group><subject>Signs and Symptoms</subject><subj-group><subject>Inflammation</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Microbiology</subject><subj-group><subject>Medical microbiology</subject><subj-group><subject>Microbial pathogens</subject><subj-group><subject>Viral pathogens</subject><subj-group><subject>Hepatitis viruses</subject><subj-group><subject>Hepatitis E virus</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and health sciences</subject><subj-group><subject>Pathology and laboratory medicine</subject><subj-group><subject>Pathogens</subject><subj-group><subject>Microbial pathogens</subject><subj-group><subject>Viral pathogens</subject><subj-group><subject>Hepatitis viruses</subject><subj-group><subject>Hepatitis E virus</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Organisms</subject><subj-group><subject>Viruses</subject><subj-group><subject>Viral pathogens</subject><subj-group><subject>Hepatitis viruses</subject><subj-group><subject>Hepatitis E virus</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and life sciences</subject><subj-group><subject>Organisms</subject><subj-group><subject>Viruses</subject><subj-group><subject>DNA viruses</subject><subj-group><subject>Herpesviruses</subject><subj-group><subject>Human Cytomegalovirus</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Microbiology</subject><subj-group><subject>Medical Microbiology</subject><subj-group><subject>Microbial Pathogens</subject><subj-group><subject>Viral Pathogens</subject><subj-group><subject>Herpesviruses</subject><subj-group><subject>Human Cytomegalovirus</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Medicine and Health Sciences</subject><subj-group><subject>Pathology and Laboratory Medicine</subject><subj-group><subject>Pathogens</subject><subj-group><subject>Microbial Pathogens</subject><subj-group><subject>Viral Pathogens</subject><subj-group><subject>Herpesviruses</subject><subj-group><subject>Human Cytomegalovirus</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v3"><subject>Biology and Life Sciences</subject><subj-group><subject>Organisms</subject><subj-group><subject>Viruses</subject><subj-group><subject>Viral Pathogens</subject><subj-group><subject>Herpesviruses</subject><subj-group><subject>Human Cytomegalovirus</subject></subj-group></subj-group></subj-group></subj-group></subj-group></subj-group></article-categories><title-group><article-title>Viral manipulation of STAT3: Evade, exploit, and injure</article-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0002-2245-3831</contrib-id><name><surname>Roca Suarez</surname><given-names>Armando Andres</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Van Renne</surname><given-names>Nicolaas</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Baumert</surname><given-names>Thomas F.</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref><xref ref-type="aff" rid="aff003"><sup>3</sup></xref></contrib><contrib contrib-type="author"><contrib-id authenticated="true" contrib-id-type="orcid">http://orcid.org/0000-0003-3996-3907</contrib-id><name><surname>Lupberger</surname><given-names>Joachim</given-names></name><xref ref-type="aff" rid="aff001"><sup>1</sup></xref><xref ref-type="aff" rid="aff002"><sup>2</sup></xref><xref ref-type="corresp" rid="cor001">*</xref></contrib></contrib-group><aff id="aff001"><label>1</label><addr-line>Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France</addr-line></aff><aff id="aff002"><label>2</label><addr-line>Université de Strasbourg, Strasbourg, France</addr-line></aff><aff id="aff003"><label>3</label><addr-line>Pôle Hépato-digestif, Institut Hospitalo-universitaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, France</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Hobman</surname><given-names>Tom C.</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>University of Alberta, CANADA</addr-line></aff><author-notes><fn fn-type="COI-statement" id="coi001"><p>The authors have declared that no competing interests exist.</p></fn><corresp id="cor001">* E-mail: <email>joachim.lupberger@unistra.fr</email></corresp></author-notes><pub-date pub-type="epub"><day>15</day><month>3</month><year>2018</year></pub-date><pub-date pub-type="collection"><month>3</month><year>2018</year></pub-date><volume>14</volume><issue>3</issue><elocation-id>e1006839</elocation-id><permissions><copyright-statement>© 2018 Roca Suarez et al</copyright-statement><copyright-year>2018</copyright-year><copyright-holder>Roca Suarez et al</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution License</ext-link>, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="ppat.1006839.pdf"></self-uri><abstract><p>Signal transducer and activator of transcription 3 (STAT3) is a key regulator of numerous physiological functions, including the immune response. As pathogens elicit an acute phase response with concerted activation of STAT3, they are confronted with two evolutionary options: either curtail it or employ it. This has important consequences for the host, since abnormal STAT3 function is associated with cancer development and other diseases. This review provides a comprehensive outline of how human viruses cope with STAT3-mediated inflammation and how this affects the host. Finally, we discuss STAT3 as a potential target for antiviral therapy.</p></abstract><funding-group><funding-statement>This work was supported by grants from the Wilhelm Sander-Stiftung (Förderantrag 2010.023.1 to TFB - <ext-link ext-link-type="uri" xlink:href="http://www.wilhelm-sander-stiftung.de">www.wilhelm-sander-stiftung.de</ext-link>), the European Union (Interreg IV-Rhin Supérieur-FEDER-Hepato-Regio-Net to TFB - <ext-link ext-link-type="uri" xlink:href="http://www.interreg-rhin-sup.eu">www.interreg-rhin-sup.eu</ext-link>; ERC-AdG-2014 HEPCIR to TFB - <ext-link ext-link-type="uri" xlink:href="http://www.cordis.europa.eu/project/rcn/198487_en.html">www.cordis.europa.eu/project/rcn/198487_en.html</ext-link>; EU H2020 HEPCAR to TFB - <ext-link ext-link-type="uri" xlink:href="http://www.hep-car.eu">www.hep-car.eu</ext-link>), the French Cancer Agency (ARC IHU201301187 to TFB - <ext-link ext-link-type="uri" xlink:href="http://www.fondation-arc.org">www.fondation-arc.org</ext-link>), the University of Strasbourg (IdEx, Projet Attractivité 2014, ANR, to JL - <ext-link ext-link-type="uri" xlink:href="http://www.en.unistra.fr">www.en.unistra.fr</ext-link>), the French ANRS (ECTZ4236, ECTZ4446 to JL and AARS - <ext-link ext-link-type="uri" xlink:href="http://www.anrs.fr">www.anrs.fr</ext-link>) and Cancéropôle Est (AAP Emergence du CGE / 2017 to JL, - <ext-link ext-link-type="uri" xlink:href="http://www.canceropole-ge.org">www.canceropole-ge.org</ext-link>). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement></funding-group><counts><fig-count count="3"></fig-count><table-count count="2"></table-count><page-count count="21"></page-count></counts></article-meta></front><body><sec id="sec001"><title>Signal transduction through the STAT3 pathway</title><sec id="sec002"><title>STAT3 is a transcription factor activated by tyrosine phosphorylation</title><p>Signal transducer and activator of transcription 3 (STAT3) was first described in 1994 as a central transcription factor in acute inflammation [<xref rid="ppat.1006839.ref001" ref-type="bibr">1</xref>]. Since then, STAT3 has been shown to regulate a wide spectrum of biological programs, including inflammation, tissue regeneration, cell proliferation, cell survival, cellular differentiation, angiogenesis, chemotaxis, and cell adhesion. This functional pleiotropy can be partially explained by the broad number of ligands that lead to STAT3 activation after binding to their respective cytokine receptors [<xref rid="ppat.1006839.ref002" ref-type="bibr">2</xref>]. Upon cytokine binding, there is typically recruitment and reciprocal trans-phosphorylation of tyrosine kinases of the Janus kinase (JAK) family comprising JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) [<xref rid="ppat.1006839.ref003" ref-type="bibr">3</xref>,<xref rid="ppat.1006839.ref004" ref-type="bibr">4</xref>,<xref rid="ppat.1006839.ref005" ref-type="bibr">5</xref>]. They, in turn, recruit and phosphorylate STAT3 (p-STAT3) at the highly conserved tyrosine residue 705 (pY705) [<xref rid="ppat.1006839.ref006" ref-type="bibr">6</xref>], resulting in the formation of STAT3 homo- or heterodimers with signal transducer and activator of transcription 1 (STAT1) or signal transducer and activator of transcription 5 (STAT5) [<xref rid="ppat.1006839.ref007" ref-type="bibr">7</xref>]. Subsequently, the activated signal transducer and activator of transcription (STAT) dimers translocate to the nucleus and facilitate gene transcription after binding to genomic DNA. Many pathways thus converge in STAT3-mediated gene-expression (<xref ref-type="fig" rid="ppat.1006839.g001">Fig 1</xref>).</p><fig id="ppat.1006839.g001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.ppat.1006839.g001</object-id><label>Fig 1</label><caption><title>Regulatory circuits of the STAT3 signaling pathway.</title><p>STAT3 can be activated by a wide range of ligands binding to cytokine, growth factor, or G-protein-coupled receptors. With the exception of receptor tyrosine kinases, these receptors lack intrinsic kinase activity and thus act by recruiting adaptor kinases (e.g., JAKs, SRC) to propagate downstream signals. As a result, STAT3 is phosphorylated at tyrosine 705 (pY705, pink), forms homodimers or heterodimers, and translocates to the nucleus, where it transcribes regulators of various cellular processes. Additionally, STAT3 can be phosphorylated at serine 727 (pS727, purple) by serine/threonine kinases (e.g., MAPK, mTOR, PKCδ), which enhance STAT3 transcriptional activity in the nucleus or direct STAT3 to mitochondria. Acetylation at lysine 685 (K685, red) by histone acetyltransferases (e.g., CREB binding protein CBP/histone acetyltransferase p300) or methylation at lysine 140 (K140, blue) by histone methyltransferases (e.g., SET9) favor or impair STAT3 transcriptional activity, respectively. Unphosphorylated STAT3 exhibits regulatory functions in the nucleus or can be retained in the cytoplasm, where it associates with microtubules and focal adhesions. The activity of STAT3 is tightly regulated by phosphatases (e.g., PTPRD), SOCS3, PIAS3, and miRNAs that fine-tune the temporal pattern of STAT3 activity and its other pathway components. All miRNAs are degrading the mRNAs of the indicated proteins. A, acetylation; CBP, CREB-binding protein; CT-1R, cardiotrophin 1 receptor; CNTFR, ciliary neurotrophic factor receptor; DUSP2, dual specificity protein phosphatase 2; EGFR, epidermal growth factor receptor; GHR, growth hormone receptor; G-CSFR, granulocyte colony-stimulating factor receptor; GM-CSFR, granulocyte-macrophage colony-stimulating factor receptor; gp130, glycoprotein 130; IFNAR, interferon alpha receptor; IFNGR, interferon gamma receptor; IL, interleukin; JAK, Janus kinase; K140, lysine 140; K685, lysine 685; LIFR, leukemia inhibitory factor receptor; MAPK, mitogen-activated protein kinase; M, methylation; miRNA, microRNA; mTOR, mechanistic target of rapamycin; OSMR, oncostatin-M-specific receptor; P, phosphorylation; p300, histone acetyltransferase p300; PDGFR, platelet-derived growth factor receptor; PIAS3, protein inhibitor of activated STAT protein 3; PKCδ, protein kinase C delta type; pS727, phospho-serine 727; PTPRC, receptor-type tyrosine-protein phosphatase C; PTPRD, receptor-type tyrosine-protein phosphatase D; PTPRT, receptor-type tyrosine-protein phosphatase T; pY705, phospho-tyrosine 705; SET9, histone-lysine N-methyltransferase SET9; SOCS3, suppressor of cytokine signaling 3; SRC, proto-oncogene tyrosine-protein kinase; STAT3, signal transducer and activator of transcription 3; TpoR, thrombopoietin receptor; TRIM28, tripartite motif-containing protein 28.</p></caption><graphic xlink:href="ppat.1006839.g001"></graphic></fig></sec><sec id="sec003"><title>Regulation of STAT3 activation</title><p>STAT3 activity is additionally regulated by several post-translational modifications. First, phosphorylation at serine 727 (pS727) by a variety of serine/threonine kinases, such as the mitogen-activated protein (MAP) kinases, mechanistic target of rapamycin (mTOR), and protein kinase C delta type (PKCδ), increases transcriptional activity even further [<xref rid="ppat.1006839.ref008" ref-type="bibr">8</xref>]. In mitochondria, pS727 promotes cellular respiration independently from pY705 [<xref rid="ppat.1006839.ref009" ref-type="bibr">9</xref>]. Second, STAT3 can be reversible acetylated on K685 by histone acetyltransferase CBP/p300, prolonging transcriptional activity [<xref rid="ppat.1006839.ref010" ref-type="bibr">10</xref>]. Contrarily, K140 methylation by histone methyltransferase SET9 impairs transcription [<xref rid="ppat.1006839.ref011" ref-type="bibr">11</xref>].</p><p>Additional negative feedback regulators include the protein phosphatases receptor-type tyrosine-protein phosphatase C (PTPRC), receptor-type tyrosine-protein phosphatase D (PTPRD), receptor-type tyrosine-protein phosphatase T (PTPRT), and dual specificity protein phosphatase 2 (DUSP2) that hydrolyze p-STAT3 or upstream pathway members [<xref rid="ppat.1006839.ref012" ref-type="bibr">12</xref>, <xref rid="ppat.1006839.ref013" ref-type="bibr">13</xref>, <xref rid="ppat.1006839.ref014" ref-type="bibr">14</xref>, <xref rid="ppat.1006839.ref015" ref-type="bibr">15</xref>]. Suppressor of cytokine signaling 3 (SOCS3) prevents STAT3 activation by shielding phospho-tyrosine residues of upstream kinases [<xref rid="ppat.1006839.ref016" ref-type="bibr">16</xref>,<xref rid="ppat.1006839.ref017" ref-type="bibr">17</xref>], while protein inhibitor of activated STAT protein 3 (PIAS3) prevents binding of STAT3 dimers to DNA [<xref rid="ppat.1006839.ref018" ref-type="bibr">18</xref>]. In the nucleus, the phosphorylation and transcriptional activity of STAT3 pS727 is negatively regulated by tripartite motif-containing protein 28 (TRIM28), which binds directly to the central coiled-coil and DNA-binding domains of STAT3 [<xref rid="ppat.1006839.ref019" ref-type="bibr">19</xref>]. Furthermore, several microRNAs (miRNAs) directly target <italic>STAT3</italic> mRNA, including Let-7a [<xref rid="ppat.1006839.ref020" ref-type="bibr">20</xref>], miR-17-5p [<xref rid="ppat.1006839.ref021" ref-type="bibr">21</xref>], miR-29b [<xref rid="ppat.1006839.ref022" ref-type="bibr">22</xref>], miR-124 [<xref rid="ppat.1006839.ref023" ref-type="bibr">23</xref>], and miR-519a [<xref rid="ppat.1006839.ref024" ref-type="bibr">24</xref>]. Let-7a also exerts an indirect effect on STAT3 by promoting SOCS3 expression [<xref rid="ppat.1006839.ref025" ref-type="bibr">25</xref>]. STAT3-activating miRNAs include miR-24 and miR-629 that impair miR-124 expression via <italic>HNF4A</italic> mRNA silencing [<xref rid="ppat.1006839.ref026" ref-type="bibr">26</xref>]. Similarly, miR-135a-5p and miR-19a enhance pY705 phosphorylation by respectively targeting the mRNA of <italic>PTPRD</italic> and <italic>SOCS3</italic> [<xref rid="ppat.1006839.ref027" ref-type="bibr">27</xref>,<xref rid="ppat.1006839.ref028" ref-type="bibr">28</xref>].</p><p>Although STAT3 phosphorylation is often considered a prerequisite for its transcriptional activity, unphosphorylated STAT3 (u-STAT3) can promote the expression of genes related to cell cycle progression [<xref rid="ppat.1006839.ref029" ref-type="bibr">29</xref>,<xref rid="ppat.1006839.ref030" ref-type="bibr">30</xref>]. Finally, cytoplasmic STAT3 promotes cell migration by interacting with stathmin, a microtubule destabilizer [<xref rid="ppat.1006839.ref031" ref-type="bibr">31</xref>].</p></sec></sec><sec id="sec004"><title>Physiological role of STAT3 in inflammation</title><p>In mammalian organisms, tissue injuries inflicted by pathogens are met by the release of inflammatory mediators and local infiltration of white blood cells. This eliminates foreign material, removes damaged tissue components, and clears the way for repair. STAT3 plays an essential role in these processes by enabling the expression of a variety of genes in response to specific external signals sensed by cell-surface receptors [<xref rid="ppat.1006839.ref032" ref-type="bibr">32</xref>]. Not all cell types and tissues have the same expression patterns of these receptors and their signaling cascade mediators. Therefore, the functional consequence of STAT3 activation is highly context-dependent, which can often lead to conflicting information. As illustrated in the following examples, this is particularly true for the role of STAT3 in inflammation, since it is either able to promote or suppress this process.</p><sec id="sec005"><title>IL-6/STAT3 pathway promotes inflammation</title><p>Interleukin 6 (IL-6) is a classic proinflammatory cytokine that signals through STAT3 as part of the acute phase response (APR), a nonspecific reaction of the innate immune system to pathogen infection. During acute inflammation, IL-6 is produced in the lesion site to attract neutrophils and increase granulopoiesis [<xref rid="ppat.1006839.ref033" ref-type="bibr">33</xref>]. Upon extravasation at the site of injury, neutrophils produce soluble interleukin 6 receptor alpha (sIL-6Rα), which in complex with IL-6 binds to glycoprotein 130 (gp130) at the membrane of resident tissue cells. This process is known as the <italic>trans</italic>-signaling pathway [<xref rid="ppat.1006839.ref034" ref-type="bibr">34</xref>], which subsequently leads to a switch in chemokine expression attracting monocytic and T cells [<xref rid="ppat.1006839.ref035" ref-type="bibr">35</xref>,<xref rid="ppat.1006839.ref036" ref-type="bibr">36</xref>]. Upon the arrival of monocytic cells in the inflammation site, IL-6 signals govern their transformation into macrophages [<xref rid="ppat.1006839.ref037" ref-type="bibr">37</xref>]. Pathogens are thus initially confronted in their initial microenvironment with a potent IL-6 stimulus, which is mounted by the host to combat their very presence.</p><p>Apart from the lesion site, the IL-6/STAT3 proinflammatory signaling axis functions in many other cellular and tissue compartments. In secondary lymphoid tissues, where the adaptive immune response takes place, IL-6-mediated STAT3 activation promotes the proliferation and survival of T and B cell populations [<xref rid="ppat.1006839.ref038" ref-type="bibr">38</xref>,<xref rid="ppat.1006839.ref039" ref-type="bibr">39</xref>]. In addition, together with transforming growth factor beta (TGF-β), the IL-6/STAT3 axis is crucial for differentiating naive CD4<sup>+</sup> T cells into Th17 cells [<xref rid="ppat.1006839.ref040" ref-type="bibr">40</xref>,<xref rid="ppat.1006839.ref041" ref-type="bibr">41</xref>], limiting the generation of regulatory CD4<sup>+</sup> T cells (T<sub>reg</sub> cells) [<xref rid="ppat.1006839.ref042" ref-type="bibr">42</xref>]. Moreover, IL-6 promotes the differentiation of follicular helper T cells (T<sub>FH</sub> cells) via STAT3 [<xref rid="ppat.1006839.ref043" ref-type="bibr">43</xref>,<xref rid="ppat.1006839.ref044" ref-type="bibr">44</xref>], effectively linking together T and B cell responses [<xref rid="ppat.1006839.ref045" ref-type="bibr">45</xref>].</p></sec><sec id="sec006"><title>IL-10/STAT3 pathway suppresses inflammation</title><p>Interleukin 10 (IL-10) also activates STAT3, but unlike IL-6 the IL-10/STAT3 axis has powerful anti-inflammatory properties. Its function is essential to restrain unwanted immune responses and prevent autoimmune pathologies [<xref rid="ppat.1006839.ref046" ref-type="bibr">46</xref>]. IL-10 only exerts an effect on immune cells, as they are the only cells to have the interleukin 10 receptor alpha (IL-10RA). This IL-10 receptor is highly expressed in monocytic cells and macrophages but also to a lesser extent in NK cells, CD4<sup>+</sup> and CD8<sup>+</sup> T cells, B cells, dendritic cells (DCs), and mast cells [<xref rid="ppat.1006839.ref047" ref-type="bibr">47</xref>]. Until recently it was unclear how, in cells responsive to both IL-6 and IL-10, STAT3 orchestrates such opposing functions. In fact, SOCS3 is critical for selecting the transcriptional response. While IL-6 signaling is selectively inhibited by SOCS3 binding to gp130, SOCS3 does not interfere with IL-10R-mediated STAT3 activation [<xref rid="ppat.1006839.ref048" ref-type="bibr">48</xref>]. As an effect, STAT3 activation is transient and proinflammatory in response to IL-6, while long lasting and anti-inflammatory in IL-10 [<xref rid="ppat.1006839.ref049" ref-type="bibr">49</xref>].</p><p>IL-10 exerts its anti-inflammatory effect by suppressing T helper 1 (T<sub>H</sub>1) cell responses [<xref rid="ppat.1006839.ref050" ref-type="bibr">50</xref>] and regulating apoptosis in B cells [<xref rid="ppat.1006839.ref051" ref-type="bibr">51</xref>]. In addition, IL-10/STAT3 is necessary for generation of tolerogenic DCs and of induced T<sub>reg</sub>s out of naïve CD4<sup>+</sup> T cells [<xref rid="ppat.1006839.ref052" ref-type="bibr">52</xref>].</p></sec><sec id="sec007"><title>Interferon activation of STAT3</title><p>Upon viral infection, type I and type II interferons (IFNs) initiate a canonical antiviral transcriptional program through STAT1 and STAT2, which results in an inflammatory, proapoptotic, and antiproliferative state [<xref rid="ppat.1006839.ref053" ref-type="bibr">53</xref>]. At the same time, IFNs induce STAT3 activation [<xref rid="ppat.1006839.ref054" ref-type="bibr">54</xref>,<xref rid="ppat.1006839.ref055" ref-type="bibr">55</xref>], which provides a negative feedback by favoring cell proliferation and survival and thus resulting in gene expression with anti-inflammatory properties [<xref rid="ppat.1006839.ref056" ref-type="bibr">56</xref>]. In support of this model, silencing of STAT1 or STAT3 expression by RNA interference confirmed the role of STATs as important determinants of IFN-α receptor (IFNAR) function [<xref rid="ppat.1006839.ref057" ref-type="bibr">57</xref>] and emphasizes the role of STAT3 to restrain STAT1-mediated proinflammatory signaling [<xref rid="ppat.1006839.ref058" ref-type="bibr">58</xref>].</p><p>In this context, an initial proinflammatory response to IFNs is mediated by STAT1, which expression is far more abundant, while STAT3-mediated gene induction is prevented by the SIN3 transcription regulator family member A complex (SIN3A). This multimolecular complex, containing histone deacetylases 1 (HDAC1) and 2 (HDAC2), inactivates STAT3 by deacetylation [<xref rid="ppat.1006839.ref059" ref-type="bibr">59</xref>]. It has been suggested that only in a second phase is STAT3 activity increased, leading to a sequential counterbalance to the initial flare of apoptosis and decrease in proliferation mediated by IFNs [<xref rid="ppat.1006839.ref060" ref-type="bibr">60</xref>].</p><p>A potential regulatory layer that remains poorly understood is the role of STAT1 and STAT3 heterodimers induced by IFNs. On one hand, STAT1 and STAT3 heterodimers have been described to bind regulatory elements present in promoters of interferon-stimulated genes (ISGs) such as γ-activated sequence (GAS), supporting a potential antiviral role of STAT1 and STAT3 heterodimers [<xref rid="ppat.1006839.ref061" ref-type="bibr">61</xref>]. On the other hand, it has been proposed that STAT1 and STAT3 heterodimers can effectively quench STAT1 and thus provide negative feedback in a later phase of the IFN response [<xref rid="ppat.1006839.ref057" ref-type="bibr">57</xref>]. Whatever the effect of STAT1 and STAT3 heterodimers on viral infection, either proviral or antiviral, it provides another layer of potential manipulation for viral gene products that warrants further research.</p><p>The suggested temporal dynamics of STAT biology may explain the serious consequences of persistent viral infections, as in the case of hepatitis C virus (HCV) [<xref rid="ppat.1006839.ref060" ref-type="bibr">60</xref>]. Here, sustained type I and II IFN signaling may drastically alter the initial STAT dimerization balance, enabling a more pronounced proliferative role of STAT3 and hence increasing oncogenic pressure on hepatocytes.</p></sec></sec><sec id="sec008"><title>Role of STAT3 in regeneration and disease</title><p>Upon infection, inflammatory cytokines trigger cell signaling in local stem cells or differentiated cells. Among other transcription factors, this eventually leads to the activation of STAT3 that mediates regenerative gene-expression programs. These genes include growth factors, cell-cycle stimulators, cell death inhibitors, and genes promoting dedifferentiation and cell motility and migration [<xref rid="ppat.1006839.ref062" ref-type="bibr">62</xref>]. The task of STAT3 in regenerative inflammation is well studied in the liver, a model for organ regeneration as it can easily restore functional capacity after partial resection through compensatory hyperplasia [<xref rid="ppat.1006839.ref063" ref-type="bibr">63</xref>,<xref rid="ppat.1006839.ref064" ref-type="bibr">64</xref>]. In the liver, the inflammatory response following injury instigates the regenerative process [<xref rid="ppat.1006839.ref065" ref-type="bibr">65</xref>]. As part of the APR, liver-residing macrophages (Kupffer cells) release proinflammatory cytokines such as IL-6 and tumor necrosis factor alpha (TNF-α) [<xref rid="ppat.1006839.ref066" ref-type="bibr">66</xref>]. These inflammatory cytokines are important components of priming pathways that help sensitize hepatocytes to proliferative signals, such as hepatocyte growth factor (HGF) and epidermal growth factor (EGF) [<xref rid="ppat.1006839.ref067" ref-type="bibr">67</xref>]. However, when liver injury persists, as in the case of chronic viral hepatitis, liver inflammation paired with constant STAT3 activity fosters the development of hepatocellular carcinoma (HCC) [<xref rid="ppat.1006839.ref027" ref-type="bibr">27</xref>]. A similar oncogenic role of STAT3 has been observed in a wide variety of other malignancies such as colorectal, lung, prostate, gastric, and breast cancers [<xref rid="ppat.1006839.ref068" ref-type="bibr">68</xref>].</p><p>Given the extensive role of STAT3 in many physiological processes, it is only logical that its perturbation entails a wide variety of pathological consequences. This is exemplified by loss-of-function mutations in the STAT3 gene that lead to the autosomal dominant hyper-immunoglobulin E (IgE) syndrome (AD-HIES) [<xref rid="ppat.1006839.ref069" ref-type="bibr">69</xref>]. These patients exhibit an immunodeficiency complex that presents with recurrent episodes of pneumonia and other lung abnormalities, abnormally high levels of IgE, eosinophilia, eczema, and skeletal and connective tissue abnormalities. Inadequate inflammatory capacity due to a broken IL-6/STAT3 axis curtails the APR and leads to "cold" skin abscesses (i.e., without inflammatory signs). As STAT3 is necessary for generating Th17 cells, a defective Th17 response and increased susceptibility for microbial infections are hallmarks of AD-HIES. On the other hand, the defects in the anti-inflammatory IL-10/STAT3 pathway lead to reduced peripheral tolerance, which is clinically translated in atopic dermatitis. Finally, AD-HIES patients exhibit a marked reduction in memory T cells and increased latency of herpesviruses such as varicella-zoster virus (VZV) and Epstein–Barr virus (EBV) [<xref rid="ppat.1006839.ref070" ref-type="bibr">70</xref>].</p></sec><sec id="sec009"><title>Molecular mechanisms of viral STAT3 manipulation</title><sec id="sec010"><title>Viral stimulation of STAT3 function</title><p>As STAT3 activation is a pivotal event in the APR elicited by pathogen invasion, many viruses have evolved to thrive in a STAT3-driven microenvironment and have developed strategies to stimulate STAT3 signaling (<xref ref-type="fig" rid="ppat.1006839.g002">Fig 2A</xref>, <xref ref-type="table" rid="ppat.1006839.t001">Table 1</xref>). For example, hepatitis B virus (HBV) promotes the formation of p-STAT3 dimers that bind specifically to an androgen-responsive element site present in the HBV enhancer 1 region and hence stimulates viral gene expression [<xref rid="ppat.1006839.ref071" ref-type="bibr">71</xref>]. This is in part mediated by hepatitis B virus X protein (HBx), which induces pY705 phosphorylation via JAK1 [<xref rid="ppat.1006839.ref072" ref-type="bibr">72</xref>] and down-regulates miRNA let-7a, a negative regulator of <italic>STAT3</italic> mRNA [<xref rid="ppat.1006839.ref020" ref-type="bibr">20</xref>]. Additionally, HBV favors STAT3 activation by inducing reactive oxygen species (ROS), which results in epigenetic silencing of <italic>SOCS3</italic> mRNA via up-regulation of snail family transcriptional repressor 1 (SNAIL1) [<xref rid="ppat.1006839.ref073" ref-type="bibr">73</xref>]. HCV requires STAT3 and therefore promotes STAT3 signaling to maintain infection [<xref rid="ppat.1006839.ref074" ref-type="bibr">74</xref>]. HCV stimulates STAT3 directly by interaction with the HCV core protein [<xref rid="ppat.1006839.ref075" ref-type="bibr">75</xref>] and indirectly through non-structural protein 5A (NS5A), which activates STAT3 via ROS induction [<xref rid="ppat.1006839.ref076" ref-type="bibr">76</xref>]. Furthermore, miR-135a-5p is a negative regulator of STAT3 phosphatase PTPRD and is up-regulated in HCV-infected hepatocytes, leading to an enhanced STAT3 transcriptional activity [<xref rid="ppat.1006839.ref027" ref-type="bibr">27</xref>]. Furthermore, HCV-infected hepatocytes secrete miR-19a within exosomes, down-regulating the expression of SOCS3 in hepatic stellate cells (HSCs) and promoting STAT3 phosphorylation [<xref rid="ppat.1006839.ref028" ref-type="bibr">28</xref>]. Similarly, Rift Valley fever virus (RVFV) infection induces STAT3 (pY705) phosphorylation by the viral non-structural protein s (NSs) [<xref rid="ppat.1006839.ref077" ref-type="bibr">77</xref>]. STAT3 activation is also a frequent feature of the Herpesviridae family. Human cytomegalovirus (HCMV) activates STAT3 through various mechanisms, depending on virus strain and cell type. In U373 MG astrocytes, viral protein US28 of the Titan strain induces IL-6 production, which in turn activates STAT3 in an auto- and paracrine fashion [<xref rid="ppat.1006839.ref078" ref-type="bibr">78</xref>]. In hepatoma cells and primary human hepatocytes (PHHs), strains AD169 and HCMV-DB also activate STAT3 via IL-6 in an autocrine and/or paracrine mannerinfluenza strain H5N1 impairs pY705 phosphorylation at I87A [<xref rid="ppat.1006839.ref087" ref-type="bibr">87</xref>]. Kaposi’s sarcoma-associated herpesvirus (KSHV) encodes a viral homologue of IL-6 (vIL-6) that signals through the same receptors as cellular IL-6 (IL-6Rα/gp130) but can also activate STAT3 in an IL-6Rα-independent manner in Hep3B liver cells [<xref rid="ppat.1006839.ref088" ref-type="bibr">88</xref>]. In human endothelial cells, KSHV increases both pY705 and pS727 phosphorylation [<xref rid="ppat.1006839.ref019" ref-type="bibr">19</xref>]. Though pY705 phosphorylation is transient, pS727 persists because the viral protein kaposin B activates the p38/MK2 pathway to suppress TRIM28, which is a negative regulator of pS727 phosphorylation [<xref rid="ppat.1006839.ref019" ref-type="bibr">19</xref>]. STAT3 activation in DCs is believed to stem from virions interacting with dendritic cell-specific ICAM-3-grabbing nonintegrin 1 (DC-SIGN) at the cell’s surface, as antibody blockage of DC-SIGN reduces pY705 levels [<xref rid="ppat.1006839.ref089" ref-type="bibr">89</xref>]. VZV induces pY705 phosphorylation in epidermal cells and T cells in vivo as well as in fibroblasts in vitro through unknown mechanisms [<xref rid="ppat.1006839.ref090" ref-type="bibr">90</xref>]. Resveratrol, an inhibitor of kinases phosphorylating STAT3, hampers VZV infection, suggesting the involvement of host kinases [<xref rid="ppat.1006839.ref091" ref-type="bibr">91</xref>]. Similarly, ZIKA virus (ZIKV) infection induces pY705 in primary retinal glial cells [<xref rid="ppat.1006839.ref092" ref-type="bibr">92</xref>] and favors the activity of the IL-6/STAT3 pathway in blood mononuclear cells from infected rhesus monkeys, albeit without any known molecular mechanism [<xref rid="ppat.1006839.ref093" ref-type="bibr">93</xref>].</p><fig id="ppat.1006839.g002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.ppat.1006839.g002</object-id><label>Fig 2</label><caption><title>Viral manipulation of the STAT3 signaling pathway.</title><p><bold>(A)</bold> Viruses activating STAT3 function and the mechanisms involved. Viral proteins such as HBx, NS5A, core, NSs, EBNA2, LMP1, US28, and IE1 induce STAT3 activation either directly or by favoring the action of upstream positive regulators. Viruses like HCMV and KSHV code for homologues of human interleukins such as IL-10 and IL-6. Alternatively, virus-induced activation of STAT3 can be achieved by the inhibition of negative regulators such as SOCS3, PTPRD, TRIM28, and Let-7a. In the case of some viruses, STAT3 activation (VZV and ZIKV) or STAT3-mediated effects (IAV) have been described, but the mechanisms involved have not been fully elucidated. All miRNAs are degrading the mRNAs of the indicated proteins. <bold>(B)</bold> Viruses suppressing STAT3 function and the mechanisms involved. Virus-mediated inactivation of STAT3 can be attained by decreasing its phosphorylation (KSHV, IAV, and hMPV), inducing STAT3 protein degradation (MuV), hampering its transcriptional activity (MeV), or altering its subcellular localization (HCMV, RABV, HEV, and hMPV). EBNA2, Epstein–Barr virus nuclear antigen 2; EBV, Epstein–Barr virus; HBV, hepatitis B virus; HBx, hepatitis B virus X protein; HCMV, human cytomegalovirus; HCV, hepatitis C virus; HEV, hepatitis E virus; hMPV, human metapneumovirus; IAV, influenza A virus; IE1, intermediate-early protein 1; IL-6, interleukin 6; IL-10, interleukin 10; IRAK1, interleukin 1 receptor-associated kinase 1; JAK1, Janus kinase 1; KSHV, Kaposi’s sarcoma-associated herpesvirus; LMP1, latent membrane protein 1; miRNA, microRNA; MeV, measles virus; MK2, mitogen-activated protein kinase 2; MuV, mumps virus; NS5A, non-structural protein 5A; NSs, non-structural proteins; P, phosphorylation; PKCδ, protein kinase C delta type; PTPRD, receptor-type tyrosine-protein phosphatase D; RABV, rabies virus; ROS, reactive oxygen species; RVFV, Rift Valley fever virus; SOCS3, suppressor of cytokine signaling 3; STAT3, signal transducer and activator of transcription 3; TRIM28, tripartite motif-containing protein 28; u-STAT3, unphosphorylated STAT3; vIL-10, viral IL-10; vIL-6, viral IL-6; VZV, varicella-zoster virus; ZIKV, Zika virus.</p></caption><graphic xlink:href="ppat.1006839.g002"></graphic></fig><table-wrap id="ppat.1006839.t001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.ppat.1006839.t001</object-id><label>Table 1</label><caption><title>Virus/STAT3 interactions: Summary of observations and employed methods.</title></caption><alternatives><graphic id="ppat.1006839.t001g" xlink:href="ppat.1006839.t001"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Virus</th><th align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Observation</th><th align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Method</th><th align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Virus strain</th><th align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Experimental system</th><th align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Reference</th></tr></thead><tbody><tr><td align="center" rowspan="3" style="background-color:#FBE4D5" valign="middle" colspan="1"><bold>HBV</bold></td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Increased STAT3 (pY705) phosphorylation</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">In vitro viral protein expression (HBx)</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">adr4-derived sequence (genotype C)</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Mouse hepatoma cell line (Hepa 1–6)</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref072" ref-type="bibr">72</xref>]</td></tr><tr><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Increased STAT3 protein and mRNA expression</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">In vitro viral protein expression (HBx)</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">adw-derived sequence (genotype A)</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Human hepatoma cell lines (HepG2, SNU-182)</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref020" ref-type="bibr">20</xref>]</td></tr><tr><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Increased STAT3 (?) phosphorylation</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">HBV-expressing cells and patient-derived samples</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">ayw (genotype D)</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Human hepatoma cell line (HepG2.2.15), HBV-positive HCC samples</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref073" ref-type="bibr">73</xref>]</td></tr><tr><td align="center" rowspan="5" style="background-color:#FBE4D5" valign="middle" colspan="1"><bold>HCV</bold></td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Increased STAT3 (pY705) phosphorylation</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">In vitro HCV genomic replicon and virus infection</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">JFH-1 (genotype 2a)</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Human hepatoma cell lines (Huh-7, NNeoC-5B)</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref074" ref-type="bibr">74</xref>]</td></tr><tr><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Increased STAT3 (pY705) phosphorylation</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">In vitro and in vivo viral protein expression (core)</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Patient-derived sequence (genotype 1b)</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Human hepatoma cell line (HepG2), Tg mice (C57BL/6)</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref075" ref-type="bibr">75</xref>]</td></tr><tr><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Increased STAT3 (pY705) phosphorylation</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">In vitro viral protein expression (NS5A)</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Patient-derived sequence (genotype 1b)</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Human hepatoma cell line (Huh-7)</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref076" ref-type="bibr">76</xref>]</td></tr><tr><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Up-regulation STAT3 responsive genes</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">In vitro HCV infection and patient-derived samples</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Jc1 (genotype 2a chimera)</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Human hepatoma cell line (Huh7.5.1) and HCV-positive HCC samples</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref027" ref-type="bibr">27</xref>]</td></tr><tr><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Increased STAT3 (?) phosphorylation</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">In vitro exposition to HCV-derived exosomes</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">JFH-1 (genotype 2a)</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Primary HSCs</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref028" ref-type="bibr">28</xref>]</td></tr><tr><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1"><bold>RVFV</bold></td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Increased STAT3 (pY705) phosphorylation</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">In vitro viral protein expression (NSs) and RVFV infection</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Recombinant MP12</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Vero cells, HSAECs, and MEFs</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref077" ref-type="bibr">77</xref>]</td></tr><tr><td align="center" rowspan="5" style="background-color:#FBE4D5" valign="middle" colspan="1"><bold>HCMV</bold></td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Increased STAT3 (pY705) phosphorylation</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">In vitro viral protein expression (US28) and HCMV infection</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Titan</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">HEK293 and astrocytoma cell line (U373 MG)</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref078" ref-type="bibr">78</xref>]</td></tr><tr><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Increased STAT3 (?) phosphorylation</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">In vitro HCMV infection</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">HCMV-AD169, HCMV-DB</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Human hepatoma cell line (HepG2) and PHHs</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref079" ref-type="bibr">79</xref>]</td></tr><tr><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Increased STAT3 (?) phosphorylation</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">In vitro vIL-10 stimulation</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1"></td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">DCs</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref081" ref-type="bibr">81</xref>]</td></tr><tr><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Increased STAT3 (pY705/pS727) phosphorylation</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">In vitro vIL-10 stimulation</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1"></td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Primary human monocytic cells</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref082" ref-type="bibr">82</xref>]</td></tr><tr><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Increased u-STAT3 nuclear localization</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">In vitro viral protein expression (IE2) and HCMV infection</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">HCMV-AD169</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Human embryonic lung fibroblasts (MRC-5) and astrocytoma cell line (U373)</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref101" ref-type="bibr">101</xref>]</td></tr><tr><td align="center" rowspan="3" style="background-color:#FBE4D5" valign="middle" colspan="1"><bold>EBV</bold></td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Increased STAT3 (pY705) phosphorylation</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">In vitro viral protein expression (LMP1) and EBV infection</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Recombinant EBV (Bx1)</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">HeLa cells, NPC cell line (CNE2)</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref083" ref-type="bibr">83</xref>]</td></tr><tr><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Increased STAT3 (pY705/pS727) phosphorylation</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">In vitro viral protein expression (LMP1)</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1"></td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Cervical carcinoma cell line (C33A)</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref084" ref-type="bibr">84</xref>]</td></tr><tr><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Increased STAT3 DNA-binding and transcriptional activity</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">In vitro viral protein expression (EBNA2)</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1"></td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">HeLa, HEK293, and human Burkitt’s lymphoma B cell line (DG75)</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref085" ref-type="bibr">85</xref>]</td></tr><tr><td align="center" rowspan="4" style="background-color:#FBE4D5" valign="middle" colspan="1"><bold>KSHV</bold></td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Increased STAT3 (pY705) phosphorylation</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">In vitro viral protein expression or stimulation (vIL-6)</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1"></td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Human hepatoma cell line (Hep3B)</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref088" ref-type="bibr">88</xref>]</td></tr><tr><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Increased STAT3 (pY705/pS727) phosphorylation</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">In vitro KSHV infection</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">BCBL-1-cell line-derived</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">HUVECs</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref019" ref-type="bibr">19</xref>]</td></tr><tr><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Increased STAT3 (pY705) phosphorylation</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">In vitro KSHV infection</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">BC3-cell line-derived</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">DCs</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref089" ref-type="bibr">89</xref>]</td></tr><tr><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Decreased STAT3 (pY705) phosphorylation</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">In vitro viral miRNAs expression</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">BCBL-1-cell line-derived</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">HUVECs</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref102" ref-type="bibr">102</xref>]</td></tr><tr><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1"><bold>VZV</bold></td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Increased STAT3 (pY705) phosphorylation</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">In vitro and in vivo VZV infection</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Recombinant VZV (ORF10-GFP)</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">HELFs, primary tonsil T cells and human skin xenografts (mouse)</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref090" ref-type="bibr">90</xref>]</td></tr><tr><td align="center" rowspan="2" style="background-color:#FBE4D5" valign="middle" colspan="1"><bold>ZIKV</bold></td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Increased STAT3 (pY705) phosphorylation</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">In vitro ZIKV infection</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">FSS13025</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Primary Müller cells (mouse)</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref092" ref-type="bibr">92</xref>]</td></tr><tr><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Increased STAT3 pathway activity</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">In vivo ZIKV infection</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Brazil-ZKV2015, PRVABC59</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">PBMCs (rhesus monkeys)</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref093" ref-type="bibr">93</xref>]</td></tr><tr><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1"><bold>MuV</bold></td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">STAT3 protein degradation</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">In vitro viral protein expression (MuV V) and MuV infection</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Enders strain</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Human fibrosarcoma-derived cell line (2fTGH)</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref094" ref-type="bibr">94</xref>]</td></tr><tr><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1"><bold>MeV</bold></td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Reduced STAT3 transcriptional activity</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">In vitro viral protein expression (MeV V)</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Edmonston strain-derived sequence</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Human fibrosarcoma-derived cell line (2fTGH)</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref095" ref-type="bibr">95</xref>]</td></tr><tr><td align="center" rowspan="2" style="background-color:#FBE4D5" valign="middle" colspan="1"><bold>IAV</bold></td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Decreased STAT3 (pY705) phosphorylation</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">In vitro IAV infection</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">H1N1/54, H5N1/483</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Alveolar epithelial cells</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref096" ref-type="bibr">96</xref>]</td></tr><tr><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Increased STAT3-dependent transcription (ANGPTL4)</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">In vivo IAV infection</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">H1N1 A/PR/8/34</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">BALB/c mice</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref103" ref-type="bibr">103</xref>]</td></tr><tr><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1"><bold>HEV</bold></td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">p-STAT3 impaired nuclear translocation</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">In vitro viral protein expression (ORF3)</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Hyderabad strain-derived sequence (genotype 1)</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Human hepatoma cell line (Huh7)</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref098" ref-type="bibr">98</xref>]</td></tr><tr><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1"><bold>RABV</bold></td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">p-STAT3 impaired nuclear translocation</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">In vitro viral protein expression (RABV P)</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">CVS strain-derived sequence</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Fibroblast-derived cell line (COS-7)</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref099" ref-type="bibr">99</xref>]</td></tr><tr><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1"><bold>hMPV</bold></td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Decreased STAT3 (pY705) phosphorylation and nuclear translocation</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">In vitro hMPV infection</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">CAN97-83</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Lung adenocarcinoma cell line (A549)</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref100" ref-type="bibr">100</xref>]</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t001fn001"><p><bold>Abbreviations:</bold> ANGPTL4, angiopoietin-like protein 4; CVS, challenge virus standard; DCs, dendritic cells; EBNA2, Epstein–Barr virus nuclear antigen 2; EBV, Epstein–Barr virus; HBV, hepatitis B virus; HBx, hepatitis B virus X protein; HCC, hepatocellular carcinoma; HCMV, human cytomegalovirus; HCV, hepatitis C virus; HELFs, human embryonic lung fibroblasts; HEV, hepatitis E virus; hMPV, human metapneumovirus; HSAECs, human small airway epithelial cells; HSCs, hepatic stellate cells; HUVECs, human umbilical vein endothelial cells; IAV, influenza A virus; IE1, intermediate-early protein 1; IE2, intermediate-early protein 2; JFH-1, Japanese fulminant hepatitis; KSHV, Kaposi’s sarcoma-associated herpesvirus; LMP1, latent membrane protein 1; MEFs, mouse embryonic fibroblasts; MeV, measles virus; MeV V, measles virus viral protein V; miRNA, microRNA; MuV, mumps virus; MuV V, mumps virus viral protein V; NPC, nasopharyngeal carcinoma; NS5A, non-structural protein 5A; NSs, non-structural proteins; PBMCs, peripheral blood mononuclear cells; PHHs, primary human hepatocytes; RABV, rabies virus; RVFV, Rift Valley fever virus; STAT3, signal transducer and activator of transcription 3; Tg, transgenic; u-STAT3, unphosphorylated STAT3; vIL-10, viral IL-10; vIL-6, viral IL-6; VZV, varicella-zoster virus; ZIKV, Zika virus.</p></fn></table-wrap-foot></table-wrap></sec><sec id="sec011"><title>Viral suppression of STAT3 function</title><p>In the acute phase, viral suppression of STAT3 reduces the host cell's ability to respond to inflammatory cytokines. On the other hand, inhibiting STAT3 also removes negative feedback on the antiviral response. To understand the beneficial effect of blocking STAT3 for viruses, it thus requires a temporal dissection of each individual virus/STAT3 interaction. Most viruses that suppress STAT3, however, do this to avoid the antiviral pressure exerted by STAT3 responsive genes in the acute phase of infection (<xref ref-type="fig" rid="ppat.1006839.g002">Fig 2B</xref>, <xref ref-type="table" rid="ppat.1006839.t001">Table 1</xref>). Mumps virus (MuV) viral protein V (MuV V) induces STAT3 degradation by promoting STAT3-directed ubiquitin E3 ligase complexes [<xref rid="ppat.1006839.ref094" ref-type="bibr">94</xref>]. Similarly, measles virus (MeV) viral protein V (MeV V) reduces STAT3-mediated transcription but through an unknown mechanism that is, however, independent of ubiquitin ligase subunits [<xref rid="ppat.1006839.ref095" ref-type="bibr">95</xref>]. Influenza A virus (IAV) infection induces STAT3 activation in the early phase of the inflammatory response. As the infection progresses, STAT3 activity is suppressed to a degree that inversely correlates with the pathogenicity of each IAV strain. For instance, the highly pathogenic avian influenza strain H5N1 impairs pY705 phosphorylation, but in the case of the low pathogenic seasonal H1N1 strain this decrease is even more pronounced [<xref rid="ppat.1006839.ref096" ref-type="bibr">96</xref>]. This inhibition could be partly mediated by viral protein NS1, which increases <italic>SOCS3</italic> expression [<xref rid="ppat.1006839.ref097" ref-type="bibr">97</xref>]. Other viruses have developed alternative strategies to impair STAT3 function, such as manipulating its subcellular localization during infection. Hepatitis E virus (HEV) ORF3 protein blocks the nuclear translocation of p-STAT3 [<xref rid="ppat.1006839.ref098" ref-type="bibr">98</xref>]. Likewise, in rabies virus (RABV) infections, viral protein P associates with p-STAT3 in the cytoplasm, impeding its nuclear translocation. In addition, P protein interferes with gp130 receptor signaling [<xref rid="ppat.1006839.ref099" ref-type="bibr">99</xref>]. Human metapneumovirus (hMPV) infection prevents the nuclear translocation of STAT3 in a cytokine-specific manner, as this was only observed following stimulation with IL-6 and not in case of interleukin 22 (IL-22) [<xref rid="ppat.1006839.ref100" ref-type="bibr">100</xref>]. Contrary to the occasions where HCMV induces STAT3 phosphorylation [<xref rid="ppat.1006839.ref078" ref-type="bibr">78</xref>,<xref rid="ppat.1006839.ref079" ref-type="bibr">79</xref>], HCMV can also rapidly disrupt IL-6/STAT3 signaling in U-373 cells by sequestering u-STAT3 to the nucleus via viral protein IE1 [<xref rid="ppat.1006839.ref101" ref-type="bibr">101</xref>]. Apart from inducing STAT3 activation, KSHV can also target and inhibit STAT3 or its activators in vitro through a panel of virally encoded miRNAs. KSHV miR-K6-5, miR-K8, and miR-K9* reduce STAT3 levels, while upon IL-6 treatment, miR-K6-5 and miR-K9 decrease PKCδ and interleukin 1 receptor-associated kinase 1 (IRAK1) expression, respectively, which is accompanied by reduced p-STAT3 levels [<xref rid="ppat.1006839.ref102" ref-type="bibr">102</xref>]. Whether in the end KSHV-induced STAT3 activation or the negative regulation of STAT3 by viral miRNAs act predominantly in endothelial cells remains unclear. But it is conceivable that both opposing mechanisms are required in a time-dependent manner to regulate the transition from the latent to the lytic stage of the viral life cycle.</p></sec></sec><sec id="sec012"><title>Consequences of viral perturbations in STAT3 activity</title><sec id="sec013"><title>Recalibration of apoptosis dynamics</title><p>Apoptosis is perhaps the most primordial response of a host cell to infection, designed to thwart the virus spread. Generally, viruses need to prevent host cell apoptosis to maintain a compartment of infected cells [<xref rid="ppat.1006839.ref104" ref-type="bibr">104</xref>]. However, there are also examples where viruses induce apoptosis to spark the release of virions and galvanize viral spread [<xref rid="ppat.1006839.ref105" ref-type="bibr">105</xref>]. STAT3 is mainly considered a negative regulator of apoptosis by up-regulating the expression of several antiapoptotic factors [<xref rid="ppat.1006839.ref106" ref-type="bibr">106</xref>] (<xref ref-type="fig" rid="ppat.1006839.g003">Fig 3A</xref>). IAV H5N1 causes higher pY705 levels than seasonal H1N1. Therefore, apoptosis is delayed during H5N1 infection, allocating additional time to infected cells for progeny virus production. Ultimately, this leads to an accumulation of apoptotic cells at later stages [<xref rid="ppat.1006839.ref096" ref-type="bibr">96</xref>]. Similarly, VZV prevents apoptosis by increasing STAT3 phosphorylation, which up-regulates baculoviral IAP repeat-containing protein 5 (<italic>BIRC5</italic>) expression, a VZV host factor belonging to the family of inhibitors of apoptosis (IAP) [<xref rid="ppat.1006839.ref090" ref-type="bibr">90</xref>]. During EBV infection, virus-induced STAT3 activation up-regulates poly(rC)-binding protein 2 (<italic>PCBP2</italic>) expression, limiting susceptibility of latently infected cells to lytic signals and fostering persistence [<xref rid="ppat.1006839.ref107" ref-type="bibr">107</xref>]. This goes as well for KSHV, in which STAT3 restrains the exit from latency into the lytic cycle by repressing the expression of the viral protein R transactivator (RTA) [<xref rid="ppat.1006839.ref108" ref-type="bibr">108</xref>]. MuV is yet another example in which the cytopathic effects of infection are associated with the induction of apoptosis, partly via V protein-mediated STAT3 degradation [<xref rid="ppat.1006839.ref094" ref-type="bibr">94</xref>]. Finally, RVFV reins in apoptosis by enhancing the nuclear translocation of phosphorylated STAT3 and impairs the expression of proapoptotic genes such as proto-oncogene c-Fos (<italic>FOS</italic>), proto-oncogene c-Jun (<italic>JUN</italic>), and nuclear receptor subfamily 4 group A member 2 (<italic>NR4A2</italic>) [<xref rid="ppat.1006839.ref077" ref-type="bibr">77</xref>].</p><fig id="ppat.1006839.g003" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.ppat.1006839.g003</object-id><label>Fig 3</label><caption><title>Viral replicative advantages and pathological consequences related to STAT3-altered function.</title><p><bold>(A)</bold> Virus-induced perturbation of STAT3 as regulator of apoptosis. In the context of viral infections, apoptosis can be restrained via STAT3, since it favors the expression of antiapoptotic factors (e.g., <italic>PCBP2</italic> and <italic>BIRC5</italic>) or prevents proapoptotic ones (e.g., RTA, <italic>FOS</italic>, <italic>JUN</italic>, and <italic>NR4A2</italic>). In contrast, inhibition of STAT3 by viruses such as IAV and MuV has been associated with the induction of the apoptotic process. <bold>(B)</bold> Viral manipulation of STAT3 and its effect on immune responses. Viral inhibition of STAT3 can induce a decrease of ISG and APR gene expression and favor immune evasion, as in the case of KSHV and HEV. Virus-mediated STAT3 activation can also have immunosuppressive actions such as impairing DC function (KSHV and HCMV) and favoring the expansion of MDSCs (HCV). In other cases, the proinflammatory actions of STAT3 have been associated with the development of host pathologies such as cancer (KSHV). <bold>(C)</bold> Virus-induced alteration of STAT3 and its impact on cell and tissue organization. STAT3 activation during HCV infection has been associated with alterations of the MT network. This represents a potential advantage for HCV by favoring virus trafficking along MTs. At the tissue and organ level, STAT3 activation has been associated with the development of fibrosis (HCV), the disruption of endothelial vascular junctions (IAV), and enhanced cell invasion, which favors cancer development (EBV). ANGPTL4, angiopoietin-like protein 4; APR, acute phase response; BIRC5, baculoviral IAP repeat-containing protein 5; CCL5, C-C motif chemokine ligand 5; DCs, dendritic cells; DC-SIGN, dendritic cell-specific ICAM-3-grabbing non-integrin 1; EBV, Epstein–Barr virus; FOS, proto-oncogene c-Fos; HCC, hepatocellular carcinoma; HCMV, human cytomegalovirus; HCV, hepatitis C virus; HEV, hepatitis E virus; HSCs, hepatic stellate cells; IAV, influenza A virus; IDO1, indoleamine 2,3-dioxygenase 1; IL-10, interleukin 10; ISG, interferon-stimulated gene; JUN, proto-oncogene c-Jun; KSHV, Kaposi’s sarcoma-associated herpesvirus; MCL1, induced myeloid leukemia cell differentiation protein Mcl-1; MDSCs, myeloid-derived suppressor cells; MT, microtubule; MUC1, mucin 1 cell surface associated; MuV, mumps virus; NPC, nasopharyngeal carcinoma; NR4A2, nuclear receptor subfamily 4 group A member 2; PCBP2, poly(rC)-binding protein 2; PD-L1, programmed cell death 1 ligand 1; RTA, R transactivator; RVFV, Rift Valley fever virus; STAT3, signal transducer and activator of transcription 3; TGF-β, transforming growth factor beta; T<sub>reg</sub>, regulatory CD4<sup>+</sup> T cell; VZV, varicella-zoster virus.</p></caption><graphic xlink:href="ppat.1006839.g003"></graphic></fig></sec><sec id="sec014"><title>Perturbing the immune response</title><p>The benefit for a virus to dampen STAT3 signaling lies in controlling antiviral innate immunity responses such as the APR (<xref ref-type="fig" rid="ppat.1006839.g003">Fig 3B</xref>). Many of the APR genes are modulators of inflammation. C-reactive protein (CRP) for example is a target gene of STAT3 and has several biological functions related to nonspecific host defense [<xref rid="ppat.1006839.ref109" ref-type="bibr">109</xref>]. Increased plasma levels of metal-binding APRs (e.g., haptoglobin and hemopexin) help protect host cells from iron loss during infection and the associated injury. Moreover, they act as scavengers for potentially damaging free oxygen radicals. Protease inhibitors among APR genes (e.g., alpha-1-antitrypsin) neutralize lysosomal proteases. These inhibiting factors are released in response to tissue infiltration of activated neutrophils and macrophages, modulating the activity of proinflammatory enzyme cascades. HEV impairs the expression of these APR genes by inhibiting STAT3, attenuating inflammatory responses and creating a favorable environment for viral replication and survival [<xref rid="ppat.1006839.ref098" ref-type="bibr">98</xref>].</p><p>In contrast to HEV, the KSHV-mediated activation of STAT3 is associated with increased expression of C-C motif chemokine ligand 5 (CCL5) [<xref rid="ppat.1006839.ref019" ref-type="bibr">19</xref>], a potent chemoattractant for monocytic cells, eosinophils, NKs, and DCs [<xref rid="ppat.1006839.ref110" ref-type="bibr">110</xref>]. Many of these cell types have been shown to be present in Kaposi’s sarcoma lesions, suggesting that STAT3 contributes to the chronic inflammatory state observed in this pathology [<xref rid="ppat.1006839.ref019" ref-type="bibr">19</xref>]. Moreover, KSHV-induced STAT3 activation correlates with up-regulated induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) expression levels, which can be reverted by inhibiting STAT3 [<xref rid="ppat.1006839.ref089" ref-type="bibr">89</xref>]. MCL1 inhibits Beclin-1, a positive regulator of autophagosome formation, to interfere with antigen processing and presentation by DCs to avoid recognition and clearance [<xref rid="ppat.1006839.ref089" ref-type="bibr">89</xref>]. KSHV also inhibits STAT3 via the action of viral miRNAs, and by doing so it hinders the expression of ISGs such as <italic>CXCL10</italic>, <italic>ISG15</italic>, <italic>IFITM1</italic>, <italic>IRF1</italic>, <italic>OAS2</italic>, and <italic>MX1</italic> [<xref rid="ppat.1006839.ref102" ref-type="bibr">102</xref>]. The vIL-10 coded by HCMV up-regulates expression of its receptor DC-SIGN in DCs, their target cells [<xref rid="ppat.1006839.ref081" ref-type="bibr">81</xref>,<xref rid="ppat.1006839.ref111" ref-type="bibr">111</xref>]. vIL-10 stimulation of DCs also prevents the expression of costimulatory molecules (i.e., CD40, CD80, and CD86), inhibiting maturation of DCs, enhancing their susceptibility to infection, and hampering the immune response [<xref rid="ppat.1006839.ref081" ref-type="bibr">81</xref>]. Chronic HCV infection has been associated with the presence of myeloid-derived suppressor cells (MDSCs), a heterogeneous population of myeloid cells that suppress the function of NK, CD4<sup>+</sup>, and CD8<sup>+</sup> T cells [<xref rid="ppat.1006839.ref112" ref-type="bibr">112</xref>]. Analysis of myeloid and lymphoid cells from chronically HCV-infected patients has shown that activation of STAT3 up-regulates the expression of suppressive genes (i.e., IL-10, programmed cell death 1 ligand 1 [PD-L1], indoleamine 2,3-dioxygenase 1 [IDO1]) in monocytic cells. They acquire MDSC-like characteristics and favor the expansion of T<sub>reg</sub> cells [<xref rid="ppat.1006839.ref113" ref-type="bibr">113</xref>,<xref rid="ppat.1006839.ref114" ref-type="bibr">114</xref>]. MDSCs have been linked to an increased tumor burden and a higher metastasis rate in patients with HCC and in liver cancer mouse models [<xref rid="ppat.1006839.ref115" ref-type="bibr">115</xref>]. Thus, by the STAT3-mediated induction of MDSCs, HCV can establish a microenvironment that supports viral immune evasion and accelerates HCC development.</p></sec><sec id="sec015"><title>Altering cell architecture and tissue organization</title><p>STAT3 also plays a role in cell morphology, which viruses exploit to promote viral persistence, with grave consequences for host cell physiology (<xref ref-type="fig" rid="ppat.1006839.g003">Fig 3C</xref>). HCV-induced p-STAT3 directly controls microtubule (MT) dynamics through contact inhibition with stathmin [<xref rid="ppat.1006839.ref074" ref-type="bibr">74</xref>]. Both HCV core and NS5A are transported along MTs [<xref rid="ppat.1006839.ref116" ref-type="bibr">116</xref>]. Moreover, HCV core integrates into the MT lattice by a direct binding to tubulin [<xref rid="ppat.1006839.ref117" ref-type="bibr">117</xref>]. Viral attenuation of stathmin enhances intracellular trafficking of the virus and increases replication [<xref rid="ppat.1006839.ref074" ref-type="bibr">74</xref>]. In addition, regenerative STAT3 activation in HSCs precipitates fibrotic gene expression (i.e., <italic>TGF-β1</italic>, <italic>TIMP-1</italic>) [<xref rid="ppat.1006839.ref028" ref-type="bibr">28</xref>], eventually leading to cirrhosis, which constitutes the procarcinogenic field on which most HCCs grow [<xref rid="ppat.1006839.ref118" ref-type="bibr">118</xref>]. IAV triggers a STAT3-mediated up-regulation of angiopoietin-like protein 4 (ANGPTL4), a protein that compromises the integrity of endothelial vascular junctions. This leads to enhanced tissue leakiness and exacerbation of inflammatory lung damage in infected mice [<xref rid="ppat.1006839.ref103" ref-type="bibr">103</xref>]. EBV is the most distinct etiological agent for the development of nasopharyngeal carcinoma (NPC), a type of cancer in which STAT3 activation or overexpression is associated with more than 75% of tumors in regions where EBV is endemic [<xref rid="ppat.1006839.ref119" ref-type="bibr">119</xref>]. EBV-mediated activation of STAT3 spurs cell invasiveness in vitro, and constitutive expression of STAT3 in NPC cell lines results in an increase of mesenchymal markers such as fibronectin and N-cadherin [<xref rid="ppat.1006839.ref120" ref-type="bibr">120</xref>]. In accordance, STAT3 activation via LMP1 induces the expression of mucin 1 cell surface-associated (MUC1), a glycoprotein involved in the early steps of cancer cell detachment [<xref rid="ppat.1006839.ref121" ref-type="bibr">121</xref>].</p></sec></sec><sec id="sec016"><title>Disruption of STAT3 function as antiviral therapy</title><p>In the cases where STAT3 activity has a proviral or pathogenic effect, blocking STAT3 represents an interesting therapeutic strategy. Unfortunately, no molecule directly targeting STAT3 has received Food and Drug Administration (FDA) approval for any pathology so far [<xref rid="ppat.1006839.ref122" ref-type="bibr">122</xref>], and candidate compounds targeting viral disease have not advanced beyond preclinical evaluation (<xref ref-type="table" rid="ppat.1006839.t002">Table 2</xref>). Small-molecule inhibitors targeting STAT3 phosphorylation (e.g., Cpd188, IB-32, Stattic) or dimerization (e.g., STA-21, S3I-201) have been evaluated as antivirals in vitro or in animal models. For instance, HCV replication but not entry is inhibited by STA-21, S3I-201, Cpd188, and IB-32 in Huh7 hepatoma cells or derivatives thereof [<xref rid="ppat.1006839.ref058" ref-type="bibr">58</xref>,<xref rid="ppat.1006839.ref074" ref-type="bibr">74</xref>,<xref rid="ppat.1006839.ref123" ref-type="bibr">123</xref>]. Similarly, S3I-201 and Stattic reduce HCMV replication in cell culture [<xref rid="ppat.1006839.ref101" ref-type="bibr">101</xref>], while S3I-201 limits VZV infection both in vitro and in animal models [<xref rid="ppat.1006839.ref090" ref-type="bibr">90</xref>]. Oligodeoxynucleotide decoys (ODNs) are DNA-binding domain inhibitors that compete for binding of transcription factors with endogenous promoter sequences in their target genes. STAT3-targeting ODNs significantly decrease HBV RNA expression and DNA replication in hepatoma cell lines [<xref rid="ppat.1006839.ref124" ref-type="bibr">124</xref>].</p><table-wrap id="ppat.1006839.t002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1371/journal.ppat.1006839.t002</object-id><label>Table 2</label><caption><title>STAT3 signaling inhibitors, their mechanisms and in vitro antiviral applications.</title></caption><alternatives><graphic id="ppat.1006839.t002g" xlink:href="ppat.1006839.t002"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col><col align="left" valign="middle" span="1"></col></colgroup><thead><tr><th align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Molecule</th><th align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Targets</th><th align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Molecule class</th><th align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Mechanism of action</th><th align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Antiviral effect</th><th align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Refs</th></tr></thead><tbody><tr><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Cpd188</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">STAT3</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Non-peptide small molecule</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Inhibition of STAT3 phosphorylation</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">HCV</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref058" ref-type="bibr">58</xref>]</td></tr><tr><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">IB-32</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">STAT3</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Non-peptide small molecule</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Inhibition of STAT3 phosphorylation</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">HCV</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref123" ref-type="bibr">123</xref>]</td></tr><tr><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">STA-21</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">STAT3</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Non-peptide small molecule</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Inhibition of STAT3 dimerization</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">HCV</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref074" ref-type="bibr">74</xref>]</td></tr><tr><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">S3I-201</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">STAT3</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Non-peptide small molecule</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Inhibition of STAT3 dimerization</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">HCV<break></break>VZV<break></break>HCMV</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref074" ref-type="bibr">74</xref>]<break></break>[<xref rid="ppat.1006839.ref090" ref-type="bibr">90</xref>]<break></break>[<xref rid="ppat.1006839.ref101" ref-type="bibr">101</xref>]</td></tr><tr><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Stattic</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">STAT3</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Non-peptide small molecule</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Inhibition of STAT3 phosphorylation</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">HCMV</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref101" ref-type="bibr">101</xref>]</td></tr><tr><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Sorafenib</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">VEGFR<break></break>PDFGR<break></break>BRAF<break></break>JAK2<break></break>STAT3</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Tyrosine kinase inhibitor</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Inhibition of STAT3 phosphorylation</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">HCMV<xref ref-type="table-fn" rid="t002fn001">*</xref></td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref130" ref-type="bibr">130</xref>]</td></tr><tr><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Resveratrol</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">JAK1<break></break>STAT3</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Natural product</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Inhibition of STAT3 phosphorylation</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">VZV<xref ref-type="table-fn" rid="t002fn001">*</xref><break></break>EBV</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref091" ref-type="bibr">91</xref>]<break></break>[<xref rid="ppat.1006839.ref126" ref-type="bibr">126</xref>,<xref rid="ppat.1006839.ref127" ref-type="bibr">127</xref>]</td></tr><tr><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Curcumin</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">JAK1<break></break>JAK2<break></break>JAK3<break></break>STAT3</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Natural product</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">Inhibition of STAT3 nuclear localization</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">HCMV</td><td align="center" style="background-color:#F4B083" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref101" ref-type="bibr">101</xref>]</td></tr><tr><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Oligodeoxynucleotide decoy</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">STAT3</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">DNA-binding modifier</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">Inhibition of STAT3 transcriptional activity</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">HBV</td><td align="center" style="background-color:#FBE4D5" valign="middle" rowspan="1" colspan="1">[<xref rid="ppat.1006839.ref124" ref-type="bibr">124</xref>]</td></tr></tbody></table></alternatives><table-wrap-foot><fn id="t002fn001"><p>*Antiviral effect via STAT3 not determined.</p></fn><fn id="t002fn002"><p><bold>Abbreviations:</bold> BRAF, serine/threonine-protein kinase B-raf; EBV, Epstein–Barr virus; HBV, hepatitis B virus; HCMV, human cytomegalovirus; HCV, hepatitis C virus; JAK1, Janus kinase 1; JAK2, Janus kinase 2; JAK3, Janus kinase 3; PDFGR, platelet-derived growth factor receptor; STAT3, signal transducer and activator of transcription 3; VEGFR, vascular endothelial growth factor receptor; VZV, varicella-zoster virus.</p></fn></table-wrap-foot></table-wrap><p>In addition, several natural products such as resveratrol or curcumin have been described to exhibit STAT3 inhibitory properties [<xref rid="ppat.1006839.ref125" ref-type="bibr">125</xref>]. Resveratrol impairs EBV and VZV infection. For EBV, at least, it has been demonstrated that resveratrol suppresses STAT3 phosphorylation [<xref rid="ppat.1006839.ref126" ref-type="bibr">126</xref>,<xref rid="ppat.1006839.ref127" ref-type="bibr">127</xref>], while the antiviral mechanism by which resveratrol inhibits VZV is not yet understood [<xref rid="ppat.1006839.ref091" ref-type="bibr">91</xref>]. Curcumin hinders HCMV replication in U373 cells by reducing nuclear accumulation of STAT3 [<xref rid="ppat.1006839.ref101" ref-type="bibr">101</xref>], and while it exerts antiviral properties for IAV [<xref rid="ppat.1006839.ref128" ref-type="bibr">128</xref>] and HCV [<xref rid="ppat.1006839.ref129" ref-type="bibr">129</xref>], a mechanistic link to STAT3 has not been demonstrated yet.</p><p>The multikinase inhibitor sorafenib exhibits an antiviral effect against various HCMV strains by inhibiting the expression of immediate early genes of HCMV at clinically relevant concentrations [<xref rid="ppat.1006839.ref130" ref-type="bibr">130</xref>]. However, sorafenib is not selective for STAT3; therefore, it is likely that a combination of unspecific effects may account for the observed antiviral effect of sorafenib on HCMV.</p></sec><sec id="sec017"><title>Outlook</title><p>STAT3 is a key regulator in inflammation and tissue regeneration triggered by almost every pathogenic infection. Therefore, viruses must deal with STAT3 activity by either curtailing it or employing it. STAT3 dependencies of viruses put a spotlight on the diverse role of signal transduction during viral infections and represent a target for potential antiviral strategies. Deregulated STAT3 signaling is an oncogenic driver and is associated with virus-induced complications, including cancers. However, targeting STAT3 during viral infection and cancer is currently an untapped reservoir, and the question still remains as to why it has not yet resulted in a broad range of clinical applications.</p><p>Currently, unspecific tyrosine kinase inhibitors (e.g., sorafenib) and monoclonal antibodies (e.g., tocilizumab) that block upstream components in the STAT3 pathway are readily administered to patients as cancer chemotherapeutics [<xref rid="ppat.1006839.ref131" ref-type="bibr">131</xref>,<xref rid="ppat.1006839.ref132" ref-type="bibr">132</xref>]. Similarly, other indirect STAT3-targeting strategies, including the modulation of STAT3 regulators, are promising. These include the use of histone deacetylase or proteasome inhibitors that promote expression of the endogenous STAT3 inhibitors SOCS3 and PIAS3, respectively [<xref rid="ppat.1006839.ref133" ref-type="bibr">133</xref>]. While the use of approved indirect STAT3 modulators in clinical practice allows an indirect safety evaluation for STAT3-targeting strategies, their use does not allow conclusions on the specific clinical tolerance and efficacy of a STAT3-based antiviral approach.</p><p>Several natural products targeting STAT3 are currently being explored and seem promising; however, many (including curcumin and resveratrol) have been described as pan-assay interference compounds (PAINs). In other words, it currently cannot be ruled out that the observed effects of these natural compounds are due to an interference with the experimental readout rather than an interaction with their specific targets [<xref rid="ppat.1006839.ref134" ref-type="bibr">134</xref>].</p><p>Due to multiple and redundant pathways that converge in STAT3 activation, direct STAT3-targeting agents would be a gold standard to assess the potential benefit of this approach. One reason why we have not observed a breakthrough in STAT3-targeting drugs so far may be that transcription factors are notoriously difficult to target and that many of the STAT3 inhibitors evaluated to date have shown to be problematic regarding their potency, bioavailability, and specificity [<xref rid="ppat.1006839.ref122" ref-type="bibr">122</xref>]. Nevertheless, as we have explored in this review, there is strong scientific rationale to continue the development of novel STAT3-targeting therapies. Recently emerged agents that appear encouraging include AZD9150, an antisense oligonucleotide targeting <italic>STAT3</italic> mRNA that is in early phase I and II studies for advanced solid and hematological cancers [<xref rid="ppat.1006839.ref135" ref-type="bibr">135</xref>–<xref rid="ppat.1006839.ref137" ref-type="bibr">137</xref>], and napabucasin, a small-molecule inhibitor that has advanced to phase III clinical trials [<xref rid="ppat.1006839.ref138" ref-type="bibr">138</xref>]. The evaluation of these and similar compounds for the treatment of cancers is expected to result in a broad range of clinical applications and holds great promise for future antiviral strategies as well.</p></sec></body><back><ack><p>We would like to thank the investigators whose work is cited here and apologize to those whose work could not be cited due to space restrictions. The authors thank <ext-link ext-link-type="uri" xlink:href="https://plus.google.com/u/0/102025334854542934976?prsrc=4">Philippe Georgel</ext-link>, Université de Strasbourg, for helpful discussions.</p></ack><ref-list><title>References</title><ref id="ppat.1006839.ref001"><label>1</label><mixed-citation publication-type="journal"><name><surname>Akira</surname><given-names>S</given-names></name>, <name><surname>Nishio</surname><given-names>Y</given-names></name>, <name><surname>Inoue</surname><given-names>M</given-names></name>, <name><surname>Wang</surname><given-names>XJ</given-names></name>, <name><surname>Wei</surname><given-names>S</given-names></name>, <etal>et al</etal> (<year>1994</year>) <article-title>Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway</article-title>. <source>Cell</source><volume>77</volume>: <fpage>63</fpage>–<lpage>71</lpage>. <pub-id pub-id-type="pmid">7512451</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref002"><label>2</label><mixed-citation publication-type="journal"><name><surname>Mackey-Lawrence</surname><given-names>NM</given-names></name>, <name><surname>Petri</surname><given-names>WA</given-names><suffix>Jr.</suffix></name> (<year>2012</year>) <article-title>Leptin and mucosal immunity</article-title>. <source>Mucosal immunology</source><volume>5</volume>: <fpage>472</fpage>–<lpage>479</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1038/mi.2012.40">10.1038/mi.2012.40</ext-link></comment><pub-id pub-id-type="pmid">22692456</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref003"><label>3</label><mixed-citation publication-type="journal"><name><surname>Wilks</surname><given-names>AF</given-names></name>, <name><surname>Harpur</surname><given-names>AG</given-names></name>, <name><surname>Kurban</surname><given-names>RR</given-names></name>, <name><surname>Ralph</surname><given-names>SJ</given-names></name>, <name><surname>Zurcher</surname><given-names>G</given-names></name>, <etal>et al</etal> (<year>1991</year>) <article-title>Two novel protein-tyrosine kinases, each with a second phosphotransferase-related catalytic domain, define a new class of protein kinase</article-title>. <source>Molecular and cellular biology</source><volume>11</volume>: <fpage>2057</fpage>–<lpage>2065</lpage>. <pub-id pub-id-type="pmid">1848670</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref004"><label>4</label><mixed-citation publication-type="journal"><name><surname>Rane</surname><given-names>SG</given-names></name>, <name><surname>Reddy</surname><given-names>EP</given-names></name> (<year>1994</year>) <article-title>JAK3: a novel JAK kinase associated with terminal differentiation of hematopoietic cells</article-title>. <source>Oncogene</source><volume>9</volume>: <fpage>2415</fpage>–<lpage>2423</lpage>. <pub-id pub-id-type="pmid">7518579</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref005"><label>5</label><mixed-citation publication-type="journal"><name><surname>Firmbach-Kraft</surname><given-names>I</given-names></name>, <name><surname>Byers</surname><given-names>M</given-names></name>, <name><surname>Shows</surname><given-names>T</given-names></name>, <name><surname>Dalla-Favera</surname><given-names>R</given-names></name>, <name><surname>Krolewski</surname><given-names>JJ</given-names></name> (<year>1990</year>) <article-title>tyk2, prototype of a novel class of non-receptor tyrosine kinase genes</article-title>. <source>Oncogene</source><volume>5</volume>: <fpage>1329</fpage>–<lpage>1336</lpage>. <pub-id pub-id-type="pmid">2216457</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref006"><label>6</label><mixed-citation publication-type="journal"><name><surname>Kaptein</surname><given-names>A</given-names></name>, <name><surname>Paillard</surname><given-names>V</given-names></name>, <name><surname>Saunders</surname><given-names>M</given-names></name> (<year>1996</year>) <article-title>Dominant negative stat3 mutant inhibits interleukin-6-induced Jak-STAT signal transduction</article-title>. <source>The Journal of biological chemistry</source><volume>271</volume>: <fpage>5961</fpage>–<lpage>5964</lpage>. <pub-id pub-id-type="pmid">8626374</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref007"><label>7</label><mixed-citation publication-type="journal"><name><surname>Delgoffe</surname><given-names>GM</given-names></name>, <name><surname>Vignali</surname><given-names>DA</given-names></name> (<year>2013</year>) <article-title>STAT heterodimers in immunity: A mixed message or a unique signal?</article-title><source>JAK-STAT</source><volume>2</volume>: <fpage>e23060</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.4161/jkst.23060">10.4161/jkst.23060</ext-link></comment><pub-id pub-id-type="pmid">24058793</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref008"><label>8</label><mixed-citation publication-type="journal"><name><surname>Wen</surname><given-names>Z</given-names></name>, <name><surname>Zhong</surname><given-names>Z</given-names></name>, <name><surname>Darnell</surname><given-names>JE</given-names><suffix>Jr.</suffix></name> (<year>1995</year>) <article-title>Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation</article-title>. <source>Cell</source><volume>82</volume>: <fpage>241</fpage>–<lpage>250</lpage>. <pub-id pub-id-type="pmid">7543024</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref009"><label>9</label><mixed-citation publication-type="journal"><name><surname>Wegrzyn</surname><given-names>J</given-names></name>, <name><surname>Potla</surname><given-names>R</given-names></name>, <name><surname>Chwae</surname><given-names>YJ</given-names></name>, <name><surname>Sepuri</surname><given-names>NB</given-names></name>, <name><surname>Zhang</surname><given-names>Q</given-names></name>, <etal>et al</etal> (<year>2009</year>) <article-title>Function of mitochondrial Stat3 in cellular respiration</article-title>. <source>Science</source><volume>323</volume>: <fpage>793</fpage>–<lpage>797</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1126/science.1164551">10.1126/science.1164551</ext-link></comment><pub-id pub-id-type="pmid">19131594</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref010"><label>10</label><mixed-citation publication-type="journal"><name><surname>Yuan</surname><given-names>ZL</given-names></name>, <name><surname>Guan</surname><given-names>YJ</given-names></name>, <name><surname>Chatterjee</surname><given-names>D</given-names></name>, <name><surname>Chin</surname><given-names>YE</given-names></name> (<year>2005</year>) <article-title>Stat3 dimerization regulated by reversible acetylation of a single lysine residue</article-title>. <source>Science</source><volume>307</volume>: <fpage>269</fpage>–<lpage>273</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1126/science.1105166">10.1126/science.1105166</ext-link></comment><pub-id pub-id-type="pmid">15653507</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref011"><label>11</label><mixed-citation publication-type="journal"><name><surname>Yang</surname><given-names>J</given-names></name>, <name><surname>Huang</surname><given-names>J</given-names></name>, <name><surname>Dasgupta</surname><given-names>M</given-names></name>, <name><surname>Sears</surname><given-names>N</given-names></name>, <name><surname>Miyagi</surname><given-names>M</given-names></name>, <etal>et al</etal> (<year>2010</year>) <article-title>Reversible methylation of promoter-bound STAT3 by histone-modifying enzymes</article-title>. <source>Proceedings of the National Academy of Sciences of the United States of America</source><volume>107</volume>: <fpage>21499</fpage>–<lpage>21504</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1073/pnas.1016147107">10.1073/pnas.1016147107</ext-link></comment><pub-id pub-id-type="pmid">21098664</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref012"><label>12</label><mixed-citation publication-type="journal"><name><surname>Kumar</surname><given-names>V</given-names></name>, <name><surname>Cheng</surname><given-names>P</given-names></name>, <name><surname>Condamine</surname><given-names>T</given-names></name>, <name><surname>Mony</surname><given-names>S</given-names></name>, <name><surname>Languino</surname><given-names>LR</given-names></name>, <etal>et al</etal> (<year>2016</year>) <article-title>CD45 Phosphatase Inhibits STAT3 Transcription Factor Activity in Myeloid Cells and Promotes Tumor-Associated Macrophage Differentiation</article-title>. <source>Immunity</source><volume>44</volume>: <fpage>303</fpage>–<lpage>315</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1016/j.immuni.2016.01.014">10.1016/j.immuni.2016.01.014</ext-link></comment><pub-id pub-id-type="pmid">26885857</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref013"><label>13</label><mixed-citation publication-type="journal"><name><surname>Veeriah</surname><given-names>S</given-names></name>, <name><surname>Brennan</surname><given-names>C</given-names></name>, <name><surname>Meng</surname><given-names>S</given-names></name>, <name><surname>Singh</surname><given-names>B</given-names></name>, <name><surname>Fagin</surname><given-names>JA</given-names></name>, <etal>et al</etal> (<year>2009</year>) <article-title>The tyrosine phosphatase PTPRD is a tumor suppressor that is frequently inactivated and mutated in glioblastoma and other human cancers</article-title>. <source>Proceedings of the National Academy of Sciences of the United States of America</source><volume>106</volume>: <fpage>9435</fpage>–<lpage>9440</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1073/pnas.0900571106">10.1073/pnas.0900571106</ext-link></comment><pub-id pub-id-type="pmid">19478061</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref014"><label>14</label><mixed-citation publication-type="journal"><name><surname>Zhang</surname><given-names>X</given-names></name>, <name><surname>Guo</surname><given-names>A</given-names></name>, <name><surname>Yu</surname><given-names>J</given-names></name>, <name><surname>Possemato</surname><given-names>A</given-names></name>, <name><surname>Chen</surname><given-names>Y</given-names></name>, <etal>et al</etal> (<year>2007</year>) <article-title>Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T</article-title>. <source>Proceedings of the National Academy of Sciences of the United States of America</source><volume>104</volume>: <fpage>4060</fpage>–<lpage>4064</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1073/pnas.0611665104">10.1073/pnas.0611665104</ext-link></comment><pub-id pub-id-type="pmid">17360477</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref015"><label>15</label><mixed-citation publication-type="journal"><name><surname>Lu</surname><given-names>D</given-names></name>, <name><surname>Liu</surname><given-names>L</given-names></name>, <name><surname>Ji</surname><given-names>X</given-names></name>, <name><surname>Gao</surname><given-names>Y</given-names></name>, <name><surname>Chen</surname><given-names>X</given-names></name>, <etal>et al</etal> (<year>2015</year>) <article-title>The phosphatase DUSP2 controls the activity of the transcription activator STAT3 and regulates TH17 differentiation</article-title>. <source>Nature immunology</source><volume>16</volume>: <fpage>1263</fpage>–<lpage>1273</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1038/ni.3278">10.1038/ni.3278</ext-link></comment><pub-id pub-id-type="pmid">26479789</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref016"><label>16</label><mixed-citation publication-type="journal"><name><surname>Nicholson</surname><given-names>SE</given-names></name>, <name><surname>De Souza</surname><given-names>D</given-names></name>, <name><surname>Fabri</surname><given-names>LJ</given-names></name>, <name><surname>Corbin</surname><given-names>J</given-names></name>, <name><surname>Willson</surname><given-names>TA</given-names></name>, <etal>et al</etal> (<year>2000</year>) <article-title>Suppressor of cytokine signaling-3 preferentially binds to the SHP-2-binding site on the shared cytokine receptor subunit gp130</article-title>. <source>Proceedings of the National Academy of Sciences of the United States of America</source><volume>97</volume>: <fpage>6493</fpage>–<lpage>6498</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1073/pnas.100135197">10.1073/pnas.100135197</ext-link></comment><pub-id pub-id-type="pmid">10829066</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref017"><label>17</label><mixed-citation publication-type="journal"><name><surname>Sasaki</surname><given-names>A</given-names></name>, <name><surname>Yasukawa</surname><given-names>H</given-names></name>, <name><surname>Suzuki</surname><given-names>A</given-names></name>, <name><surname>Kamizono</surname><given-names>S</given-names></name>, <name><surname>Syoda</surname><given-names>T</given-names></name>, <etal>et al</etal> (<year>1999</year>) <article-title>Cytokine-inducible SH2 protein-3 (CIS3/SOCS3) inhibits Janus tyrosine kinase by binding through the N-terminal kinase inhibitory region as well as SH2 domain</article-title>. <source>Genes to cells: devoted to molecular & cellular mechanisms</source><volume>4</volume>: <fpage>339</fpage>–<lpage>351</lpage>.<pub-id pub-id-type="pmid">10421843</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref018"><label>18</label><mixed-citation publication-type="journal"><name><surname>Chung</surname><given-names>CD</given-names></name>, <name><surname>Liao</surname><given-names>J</given-names></name>, <name><surname>Liu</surname><given-names>B</given-names></name>, <name><surname>Rao</surname><given-names>X</given-names></name>, <name><surname>Jay</surname><given-names>P</given-names></name>, <etal>et al</etal> (<year>1997</year>) <article-title>Specific inhibition of Stat3 signal transduction by PIAS3</article-title>. <source>Science</source><volume>278</volume>: <fpage>1803</fpage>–<lpage>1805</lpage>. <pub-id pub-id-type="pmid">9388184</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref019"><label>19</label><mixed-citation publication-type="journal"><name><surname>King</surname><given-names>CA</given-names></name> (<year>2013</year>) <article-title>Kaposi's sarcoma-associated herpesvirus kaposin B induces unique monophosphorylation of STAT3 at serine 727 and MK2-mediated inactivation of the STAT3 transcriptional repressor TRIM28</article-title>. <source>J Virol</source><volume>87</volume>: <fpage>8779</fpage>–<lpage>8791</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/JVI.02976-12">10.1128/JVI.02976-12</ext-link></comment><pub-id pub-id-type="pmid">23740979</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref020"><label>20</label><mixed-citation publication-type="journal"><name><surname>Wang</surname><given-names>Y</given-names></name>, <name><surname>Lu</surname><given-names>Y</given-names></name>, <name><surname>Toh</surname><given-names>ST</given-names></name>, <name><surname>Sung</surname><given-names>WK</given-names></name>, <name><surname>Tan</surname><given-names>P</given-names></name>, <etal>et al</etal> (<year>2010</year>) <article-title>Lethal-7 is down-regulated by the hepatitis B virus x protein and targets signal transducer and activator of transcription 3</article-title>. <source>Journal of hepatology</source><volume>53</volume>: <fpage>57</fpage>–<lpage>66</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1016/j.jhep.2009.12.043">10.1016/j.jhep.2009.12.043</ext-link></comment><pub-id pub-id-type="pmid">20447714</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref021"><label>21</label><mixed-citation publication-type="journal"><name><surname>Liao</surname><given-names>XH</given-names></name>, <name><surname>Xiang</surname><given-names>Y</given-names></name>, <name><surname>Yu</surname><given-names>CX</given-names></name>, <name><surname>Li</surname><given-names>JP</given-names></name>, <name><surname>Li</surname><given-names>H</given-names></name>, <etal>et al</etal> (<year>2017</year>) <article-title>STAT3 is required for MiR-17-5p-mediated sensitization to chemotherapy-induced apoptosis in breast cancer cells</article-title>. <source>Oncotarget</source><volume>8</volume>: <fpage>15763</fpage>–<lpage>15774</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.18632/oncotarget.15000">10.18632/oncotarget.15000</ext-link></comment><pub-id pub-id-type="pmid">28178652</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref022"><label>22</label><mixed-citation publication-type="journal"><name><surname>Qin</surname><given-names>L</given-names></name>, <name><surname>Li</surname><given-names>R</given-names></name>, <name><surname>Zhang</surname><given-names>J</given-names></name>, <name><surname>Li</surname><given-names>A</given-names></name>, <name><surname>Luo</surname><given-names>R</given-names></name> (<year>2015</year>) <article-title>Special suppressive role of miR-29b in HER2-positive breast cancer cells by targeting Stat3</article-title>. <source>American journal of translational research</source><volume>7</volume>: <fpage>878</fpage>–<lpage>890</lpage>. <pub-id pub-id-type="pmid">26175849</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref023"><label>23</label><mixed-citation publication-type="journal"><name><surname>Cheng</surname><given-names>Y</given-names></name>, <name><surname>Li</surname><given-names>Y</given-names></name>, <name><surname>Nian</surname><given-names>Y</given-names></name>, <name><surname>Liu</surname><given-names>D</given-names></name>, <name><surname>Dai</surname><given-names>F</given-names></name>, <etal>et al</etal> (<year>2015</year>) <article-title>STAT3 is involved in miR-124-mediated suppressive effects on esophageal cancer cells</article-title>. <source>BMC cancer</source><volume>15</volume>: <fpage>306</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1186/s12885-015-1303-0">10.1186/s12885-015-1303-0</ext-link></comment><pub-id pub-id-type="pmid">25928665</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref024"><label>24</label><mixed-citation publication-type="journal"><name><surname>Hong</surname><given-names>L</given-names></name>, <name><surname>Ya-Wei</surname><given-names>L</given-names></name>, <name><surname>Hai</surname><given-names>W</given-names></name>, <name><surname>Qiang</surname><given-names>Z</given-names></name>, <name><surname>Jun-Jie</surname><given-names>L</given-names></name>, <etal>et al</etal> (<year>2016</year>) <article-title>MiR-519a functions as a tumor suppressor in glioma by targeting the oncogenic STAT3 pathway</article-title>. <source>Journal of neuro-oncology</source><volume>128</volume>: <fpage>35</fpage>–<lpage>45</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1007/s11060-016-2095-z">10.1007/s11060-016-2095-z</ext-link></comment><pub-id pub-id-type="pmid">26970980</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref025"><label>25</label><mixed-citation publication-type="journal"><name><surname>Patel</surname><given-names>K</given-names></name>, <name><surname>Kollory</surname><given-names>A</given-names></name>, <name><surname>Takashima</surname><given-names>A</given-names></name>, <name><surname>Sarkar</surname><given-names>S</given-names></name>, <name><surname>Faller</surname><given-names>DV</given-names></name>, <etal>et al</etal> (<year>2014</year>) <article-title>MicroRNA let-7 downregulates STAT3 phosphorylation in pancreatic cancer cells by increasing SOCS3 expression</article-title>. <source>Cancer letters</source><volume>347</volume>: <fpage>54</fpage>–<lpage>64</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1016/j.canlet.2014.01.020">10.1016/j.canlet.2014.01.020</ext-link></comment><pub-id pub-id-type="pmid">24491408</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref026"><label>26</label><mixed-citation publication-type="journal"><name><surname>Hatziapostolou</surname><given-names>M</given-names></name>, <name><surname>Polytarchou</surname><given-names>C</given-names></name>, <name><surname>Aggelidou</surname><given-names>E</given-names></name>, <name><surname>Drakaki</surname><given-names>A</given-names></name>, <name><surname>Poultsides</surname><given-names>GA</given-names></name>, <etal>et al</etal> (<year>2011</year>) <article-title>An HNF4alpha-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis</article-title>. <source>Cell</source><volume>147</volume>: <fpage>1233</fpage>–<lpage>1247</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1016/j.cell.2011.10.043">10.1016/j.cell.2011.10.043</ext-link></comment><pub-id pub-id-type="pmid">22153071</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref027"><label>27</label><mixed-citation publication-type="journal"><name><surname>Van Renne</surname><given-names>N</given-names></name>, <name><surname>Roca Suarez</surname><given-names>AA</given-names></name>, <name><surname>Duong</surname><given-names>FH</given-names></name>, <name><surname>Gondeau</surname><given-names>C</given-names></name>, <name><surname>Calabrese</surname><given-names>D</given-names></name>, <etal>et al</etal> (<year>2017</year>) <article-title>miR-135a-5p-mediated downregulation of protein tyrosine phosphatase receptor delta is a candidate driver of HCV-associated hepatocarcinogenesis</article-title>. <source>Gut</source> pii: gutjnl-2016-312270.</mixed-citation></ref><ref id="ppat.1006839.ref028"><label>28</label><mixed-citation publication-type="journal"><name><surname>Devhare</surname><given-names>PB</given-names></name>, <name><surname>Sasaki</surname><given-names>R</given-names></name>, <name><surname>Shrivastava</surname><given-names>S</given-names></name>, <name><surname>Di Bisceglie</surname><given-names>AM</given-names></name>, <name><surname>Ray</surname><given-names>R</given-names></name>, <etal>et al</etal> (<year>2017</year>) <article-title>Exosome-Mediated Intercellular Communication between Hepatitis C Virus-Infected Hepatocytes and Hepatic Stellate Cells</article-title>. <source>J Virol</source><volume>91</volume>.</mixed-citation></ref><ref id="ppat.1006839.ref029"><label>29</label><mixed-citation publication-type="journal"><name><surname>Yang</surname><given-names>J</given-names></name>, <name><surname>Chatterjee-Kishore</surname><given-names>M</given-names></name>, <name><surname>Staugaitis</surname><given-names>SM</given-names></name>, <name><surname>Nguyen</surname><given-names>H</given-names></name>, <name><surname>Schlessinger</surname><given-names>K</given-names></name>, <etal>et al</etal> (<year>2005</year>) <article-title>Novel roles of unphosphorylated STAT3 in oncogenesis and transcriptional regulation</article-title>. <source>Cancer research</source><volume>65</volume>: <fpage>939</fpage>–<lpage>947</lpage>. <pub-id pub-id-type="pmid">15705894</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref030"><label>30</label><mixed-citation publication-type="journal"><name><surname>Yang</surname><given-names>J</given-names></name>, <name><surname>Liao</surname><given-names>X</given-names></name>, <name><surname>Agarwal</surname><given-names>MK</given-names></name>, <name><surname>Barnes</surname><given-names>L</given-names></name>, <name><surname>Auron</surname><given-names>PE</given-names></name>, <etal>et al</etal> (<year>2007</year>) <article-title>Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB</article-title>. <source>Genes & development</source><volume>21</volume>: <fpage>1396</fpage>–<lpage>1408</lpage>.<pub-id pub-id-type="pmid">17510282</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref031"><label>31</label><mixed-citation publication-type="journal"><name><surname>Ng</surname><given-names>DC</given-names></name>, <name><surname>Lin</surname><given-names>BH</given-names></name>, <name><surname>Lim</surname><given-names>CP</given-names></name>, <name><surname>Huang</surname><given-names>G</given-names></name>, <name><surname>Zhang</surname><given-names>T</given-names></name>, <etal>et al</etal> (<year>2006</year>) <article-title>Stat3 regulates microtubules by antagonizing the depolymerization activity of stathmin</article-title>. <source>The Journal of cell biology</source><volume>172</volume>: <fpage>245</fpage>–<lpage>257</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1083/jcb.200503021">10.1083/jcb.200503021</ext-link></comment><pub-id pub-id-type="pmid">16401721</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref032"><label>32</label><mixed-citation publication-type="journal"><name><surname>Sehgal</surname><given-names>PB</given-names></name> (<year>2008</year>) <article-title>Paradigm shifts in the cell biology of STAT signaling</article-title>. <source>Seminars in cell & developmental biology</source><volume>19</volume>: <fpage>329</fpage>–<lpage>340</lpage>.<pub-id pub-id-type="pmid">18691663</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref033"><label>33</label><mixed-citation publication-type="journal"><name><surname>Liu</surname><given-names>F</given-names></name>, <name><surname>Poursine-Laurent</surname><given-names>J</given-names></name>, <name><surname>Wu</surname><given-names>HY</given-names></name>, <name><surname>Link</surname><given-names>DC</given-names></name> (<year>1997</year>) <article-title>Interleukin-6 and the granulocyte colony-stimulating factor receptor are major independent regulators of granulopoiesis in vivo but are not required for lineage commitment or terminal differentiation</article-title>. <source>Blood</source><volume>90</volume>: <fpage>2583</fpage>–<lpage>2590</lpage>. <pub-id pub-id-type="pmid">9326224</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref034"><label>34</label><mixed-citation publication-type="journal"><name><surname>Hurst</surname><given-names>SM</given-names></name>, <name><surname>Wilkinson</surname><given-names>TS</given-names></name>, <name><surname>McLoughlin</surname><given-names>RM</given-names></name>, <name><surname>Jones</surname><given-names>S</given-names></name>, <name><surname>Horiuchi</surname><given-names>S</given-names></name>, <etal>et al</etal> (<year>2001</year>) <article-title>Il-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation</article-title>. <source>Immunity</source><volume>14</volume>: <fpage>705</fpage>–<lpage>714</lpage>. <pub-id pub-id-type="pmid">11420041</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref035"><label>35</label><mixed-citation publication-type="journal"><name><surname>McLoughlin</surname><given-names>RM</given-names></name>, <name><surname>Jenkins</surname><given-names>BJ</given-names></name>, <name><surname>Grail</surname><given-names>D</given-names></name>, <name><surname>Williams</surname><given-names>AS</given-names></name>, <name><surname>Fielding</surname><given-names>CA</given-names></name>, <etal>et al</etal> (<year>2005</year>) <article-title>IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation</article-title>. <source>Proceedings of the National Academy of Sciences of the United States of America</source><volume>102</volume>: <fpage>9589</fpage>–<lpage>9594</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1073/pnas.0501794102">10.1073/pnas.0501794102</ext-link></comment><pub-id pub-id-type="pmid">15976028</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref036"><label>36</label><mixed-citation publication-type="journal"><name><surname>Romano</surname><given-names>M</given-names></name>, <name><surname>Sironi</surname><given-names>M</given-names></name>, <name><surname>Toniatti</surname><given-names>C</given-names></name>, <name><surname>Polentarutti</surname><given-names>N</given-names></name>, <name><surname>Fruscella</surname><given-names>P</given-names></name>, <etal>et al</etal> (<year>1997</year>) <article-title>Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment</article-title>. <source>Immunity</source><volume>6</volume>: <fpage>315</fpage>–<lpage>325</lpage>. <pub-id pub-id-type="pmid">9075932</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref037"><label>37</label><mixed-citation publication-type="journal"><name><surname>Chomarat</surname><given-names>P</given-names></name>, <name><surname>Banchereau</surname><given-names>J</given-names></name>, <name><surname>Davoust</surname><given-names>J</given-names></name>, <name><surname>Palucka</surname><given-names>AK</given-names></name> (<year>2000</year>) <article-title>IL-6 switches the differentiation of monocytes from dendritic cells to macrophages</article-title>. <source>Nat Immunol</source><volume>1</volume>: <fpage>510</fpage>–<lpage>514</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1038/82763">10.1038/82763</ext-link></comment><pub-id pub-id-type="pmid">11101873</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref038"><label>38</label><mixed-citation publication-type="journal"><name><surname>Rochman</surname><given-names>I</given-names></name>, <name><surname>Paul</surname><given-names>WE</given-names></name>, <name><surname>Ben-Sasson</surname><given-names>SZ</given-names></name> (<year>2005</year>) <article-title>IL-6 increases primed cell expansion and survival</article-title>. <source>Journal of immunology</source><volume>174</volume>: <fpage>4761</fpage>–<lpage>4767</lpage>.</mixed-citation></ref><ref id="ppat.1006839.ref039"><label>39</label><mixed-citation publication-type="journal"><name><surname>Yu</surname><given-names>CR</given-names></name>, <name><surname>Dambuza</surname><given-names>IM</given-names></name>, <name><surname>Lee</surname><given-names>YJ</given-names></name>, <name><surname>Frank</surname><given-names>GM</given-names></name>, <name><surname>Egwuagu</surname><given-names>CE</given-names></name> (<year>2013</year>) <article-title>STAT3 regulates proliferation and survival of CD8+ T cells: enhances effector responses to HSV-1 infection, and inhibits IL-10+ regulatory CD8+ T cells in autoimmune uveitis</article-title>. <source>Mediators of inflammation</source><volume>2013</volume>: <fpage>359674</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1155/2013/359674">10.1155/2013/359674</ext-link></comment><pub-id pub-id-type="pmid">24204098</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref040"><label>40</label><mixed-citation publication-type="journal"><name><surname>Ivanov</surname><given-names>II</given-names></name>, <name><surname>McKenzie</surname><given-names>BS</given-names></name>, <name><surname>Zhou</surname><given-names>L</given-names></name>, <name><surname>Tadokoro</surname><given-names>CE</given-names></name>, <name><surname>Lepelley</surname><given-names>A</given-names></name>, <etal>et al</etal> (<year>2006</year>) <article-title>The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells</article-title>. <source>Cell</source><volume>126</volume>: <fpage>1121</fpage>–<lpage>1133</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1016/j.cell.2006.07.035">10.1016/j.cell.2006.07.035</ext-link></comment><pub-id pub-id-type="pmid">16990136</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref041"><label>41</label><mixed-citation publication-type="journal"><name><surname>Nowell</surname><given-names>MA</given-names></name>, <name><surname>Williams</surname><given-names>AS</given-names></name>, <name><surname>Carty</surname><given-names>SA</given-names></name>, <name><surname>Scheller</surname><given-names>J</given-names></name>, <name><surname>Hayes</surname><given-names>AJ</given-names></name>, <etal>et al</etal> (<year>2009</year>) <article-title>Therapeutic targeting of IL-6 trans signaling counteracts STAT3 control of experimental inflammatory arthritis</article-title>. <source>Journal of immunology</source><volume>182</volume>: <fpage>613</fpage>–<lpage>622</lpage>.</mixed-citation></ref><ref id="ppat.1006839.ref042"><label>42</label><mixed-citation publication-type="journal"><name><surname>Korn</surname><given-names>T</given-names></name>, <name><surname>Mitsdoerffer</surname><given-names>M</given-names></name>, <name><surname>Croxford</surname><given-names>AL</given-names></name>, <name><surname>Awasthi</surname><given-names>A</given-names></name>, <name><surname>Dardalhon</surname><given-names>VA</given-names></name>, <etal>et al</etal> (<year>2008</year>) <article-title>IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells</article-title>. <source>Proceedings of the National Academy of Sciences of the United States of America</source><volume>105</volume>: <fpage>18460</fpage>–<lpage>18465</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1073/pnas.0809850105">10.1073/pnas.0809850105</ext-link></comment><pub-id pub-id-type="pmid">19015529</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref043"><label>43</label><mixed-citation publication-type="journal"><name><surname>Eto</surname><given-names>D</given-names></name>, <name><surname>Lao</surname><given-names>C</given-names></name>, <name><surname>DiToro</surname><given-names>D</given-names></name>, <name><surname>Barnett</surname><given-names>B</given-names></name>, <name><surname>Escobar</surname><given-names>TC</given-names></name>, <etal>et al</etal> (<year>2011</year>) <article-title>IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation</article-title>. <source>PLoS ONE</source><volume>6</volume>: <fpage>e17739</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1371/journal.pone.0017739">10.1371/journal.pone.0017739</ext-link></comment><pub-id pub-id-type="pmid">21423809</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref044"><label>44</label><mixed-citation publication-type="journal"><name><surname>Ma</surname><given-names>CS</given-names></name>, <name><surname>Avery</surname><given-names>DT</given-names></name>, <name><surname>Chan</surname><given-names>A</given-names></name>, <name><surname>Batten</surname><given-names>M</given-names></name>, <name><surname>Bustamante</surname><given-names>J</given-names></name>, <etal>et al</etal> (<year>2012</year>) <article-title>Functional STAT3 deficiency compromises the generation of human T follicular helper cells</article-title>. <source>Blood</source><volume>119</volume>: <fpage>3997</fpage>–<lpage>4008</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1182/blood-2011-11-392985">10.1182/blood-2011-11-392985</ext-link></comment><pub-id pub-id-type="pmid">22403255</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref045"><label>45</label><mixed-citation publication-type="journal"><name><surname>Ma</surname><given-names>CS</given-names></name>, <name><surname>Deenick</surname><given-names>EK</given-names></name>, <name><surname>Batten</surname><given-names>M</given-names></name>, <name><surname>Tangye</surname><given-names>SG</given-names></name> (<year>2012</year>) <article-title>The origins, function, and regulation of T follicular helper cells</article-title>. <source>The Journal of experimental medicine</source><volume>209</volume>: <fpage>1241</fpage>–<lpage>1253</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1084/jem.20120994">10.1084/jem.20120994</ext-link></comment><pub-id pub-id-type="pmid">22753927</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref046"><label>46</label><mixed-citation publication-type="journal"><name><surname>Ouyang</surname><given-names>W</given-names></name>, <name><surname>Rutz</surname><given-names>S</given-names></name>, <name><surname>Crellin</surname><given-names>NK</given-names></name>, <name><surname>Valdez</surname><given-names>PA</given-names></name>, <name><surname>Hymowitz</surname><given-names>SG</given-names></name> (<year>2011</year>) <article-title>Regulation and functions of the IL-10 family of cytokines in inflammation and disease</article-title>. <source>Annual review of immunology</source><volume>29</volume>: <fpage>71</fpage>–<lpage>109</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1146/annurev-immunol-031210-101312">10.1146/annurev-immunol-031210-101312</ext-link></comment><pub-id pub-id-type="pmid">21166540</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref047"><label>47</label><mixed-citation publication-type="journal"><name><surname>Wu</surname><given-names>C</given-names></name>, <name><surname>Orozco</surname><given-names>C</given-names></name>, <name><surname>Boyer</surname><given-names>J</given-names></name>, <name><surname>Leglise</surname><given-names>M</given-names></name>, <name><surname>Goodale</surname><given-names>J</given-names></name>, <etal>et al</etal> (<year>2009</year>) <article-title>BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources</article-title>. <source>Genome Biol</source><volume>10</volume>: <fpage>R130</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1186/gb-2009-10-11-r130">10.1186/gb-2009-10-11-r130</ext-link></comment><pub-id pub-id-type="pmid">19919682</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref048"><label>48</label><mixed-citation publication-type="journal"><name><surname>Yasukawa</surname><given-names>H</given-names></name>, <name><surname>Ohishi</surname><given-names>M</given-names></name>, <name><surname>Mori</surname><given-names>H</given-names></name>, <name><surname>Murakami</surname><given-names>M</given-names></name>, <name><surname>Chinen</surname><given-names>T</given-names></name>, <etal>et al</etal> (<year>2003</year>) <article-title>IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages</article-title>. <source>Nature immunology</source><volume>4</volume>: <fpage>551</fpage>–<lpage>556</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1038/ni938">10.1038/ni938</ext-link></comment><pub-id pub-id-type="pmid">12754507</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref049"><label>49</label><mixed-citation publication-type="journal"><name><surname>Yoshimura</surname><given-names>A</given-names></name>, <name><surname>Naka</surname><given-names>T</given-names></name>, <name><surname>Kubo</surname><given-names>M</given-names></name> (<year>2007</year>) <article-title>SOCS proteins, cytokine signalling and immune regulation</article-title>. <source>Nature reviews Immunology</source><volume>7</volume>: <fpage>454</fpage>–<lpage>465</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1038/nri2093">10.1038/nri2093</ext-link></comment><pub-id pub-id-type="pmid">17525754</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref050"><label>50</label><mixed-citation publication-type="journal"><name><surname>Cavani</surname><given-names>A</given-names></name>, <name><surname>Nasorri</surname><given-names>F</given-names></name>, <name><surname>Prezzi</surname><given-names>C</given-names></name>, <name><surname>Sebastiani</surname><given-names>S</given-names></name>, <name><surname>Albanesi</surname><given-names>C</given-names></name>, <etal>et al</etal> (<year>2000</year>) <article-title>Human CD4+ T lymphocytes with remarkable regulatory functions on dendritic cells and nickel-specific Th1 immune responses</article-title>. <source>J Invest Dermatol</source><volume>114</volume>: <fpage>295</fpage>–<lpage>302</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1046/j.1523-1747.2000.00881.x">10.1046/j.1523-1747.2000.00881.x</ext-link></comment><pub-id pub-id-type="pmid">10651989</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref051"><label>51</label><mixed-citation publication-type="journal"><name><surname>Itoh</surname><given-names>K</given-names></name>, <name><surname>Hirohata</surname><given-names>S</given-names></name> (<year>1995</year>) <article-title>The role of IL-10 in human B cell activation, proliferation, and differentiation</article-title>. <source>J Immunol</source><volume>154</volume>: <fpage>4341</fpage>–<lpage>4350</lpage>. <pub-id pub-id-type="pmid">7722292</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref052"><label>52</label><mixed-citation publication-type="journal"><name><surname>Saito</surname><given-names>M</given-names></name>, <name><surname>Nagasawa</surname><given-names>M</given-names></name>, <name><surname>Takada</surname><given-names>H</given-names></name>, <name><surname>Hara</surname><given-names>T</given-names></name>, <name><surname>Tsuchiya</surname><given-names>S</given-names></name>, <etal>et al</etal> (<year>2011</year>) <article-title>Defective IL-10 signaling in hyper-IgE syndrome results in impaired generation of tolerogenic dendritic cells and induced regulatory T cells</article-title>. <source>J Exp Med</source><volume>208</volume>: <fpage>235</fpage>–<lpage>249</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1084/jem.20100799">10.1084/jem.20100799</ext-link></comment><pub-id pub-id-type="pmid">21300911</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref053"><label>53</label><mixed-citation publication-type="journal"><name><surname>Raftery</surname><given-names>N</given-names></name>, <name><surname>Stevenson</surname><given-names>NJ</given-names></name> (<year>2017</year>) <article-title>Advances in anti-viral immune defence: revealing the importance of the IFN JAK/STAT pathway</article-title>. <source>Cell Mol Life Sci</source><volume>74</volume>: <fpage>2525</fpage>–<lpage>2535</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1007/s00018-017-2520-2">10.1007/s00018-017-2520-2</ext-link></comment><pub-id pub-id-type="pmid">28432378</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref054"><label>54</label><mixed-citation publication-type="journal"><name><surname>Darnell</surname><given-names>JE</given-names><suffix>Jr.</suffix></name>, <name><surname>Kerr</surname><given-names>IM</given-names></name>, <name><surname>Stark</surname><given-names>GR</given-names></name> (<year>1994</year>) <article-title>Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins</article-title>. <source>Science</source><volume>264</volume>: <fpage>1415</fpage>–<lpage>1421</lpage>. <pub-id pub-id-type="pmid">8197455</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref055"><label>55</label><mixed-citation publication-type="journal"><name><surname>Velichko</surname><given-names>S</given-names></name>, <name><surname>Wagner</surname><given-names>TC</given-names></name>, <name><surname>Turkson</surname><given-names>J</given-names></name>, <name><surname>Jove</surname><given-names>R</given-names></name>, <name><surname>Croze</surname><given-names>E</given-names></name> (<year>2002</year>) <article-title>STAT3 activation by type I interferons is dependent on specific tyrosines located in the cytoplasmic domain of interferon receptor chain 2c. Activation of multiple STATS proceeds through the redundant usage of two tyrosine residues</article-title>. <source>The Journal of biological chemistry</source><volume>277</volume>: <fpage>35635</fpage>–<lpage>35641</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1074/jbc.M204578200">10.1074/jbc.M204578200</ext-link></comment><pub-id pub-id-type="pmid">12105218</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref056"><label>56</label><mixed-citation publication-type="journal"><name><surname>Wang</surname><given-names>WB</given-names></name>, <name><surname>Levy</surname><given-names>DE</given-names></name>, <name><surname>Lee</surname><given-names>CK</given-names></name> (<year>2011</year>) <article-title>STAT3 negatively regulates type I IFN-mediated antiviral response</article-title>. <source>Journal of immunology</source><volume>187</volume>: <fpage>2578</fpage>–<lpage>2585</lpage>.</mixed-citation></ref><ref id="ppat.1006839.ref057"><label>57</label><mixed-citation publication-type="journal"><name><surname>Ho</surname><given-names>HH</given-names></name>, <name><surname>Ivashkiv</surname><given-names>LB</given-names></name> (<year>2006</year>) <article-title>Role of STAT3 in type I interferon responses. Negative regulation of STAT1-dependent inflammatory gene activation</article-title>. <source>The Journal of biological chemistry</source><volume>281</volume>: <fpage>14111</fpage>–<lpage>14118</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1074/jbc.M511797200">10.1074/jbc.M511797200</ext-link></comment><pub-id pub-id-type="pmid">16571725</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref058"><label>58</label><mixed-citation publication-type="journal"><name><surname>Lupberger</surname><given-names>J</given-names></name>, <name><surname>Duong</surname><given-names>FH</given-names></name>, <name><surname>Fofana</surname><given-names>I</given-names></name>, <name><surname>Zona</surname><given-names>L</given-names></name>, <name><surname>Xiao</surname><given-names>F</given-names></name>, <etal>et al</etal> (<year>2013</year>) <article-title>Epidermal growth factor receptor signaling impairs the antiviral activity of interferon-alpha</article-title>. <source>Hepatology</source><volume>58</volume>: <fpage>1225</fpage>–<lpage>1235</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1002/hep.26404">10.1002/hep.26404</ext-link></comment><pub-id pub-id-type="pmid">23519785</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref059"><label>59</label><mixed-citation publication-type="journal"><name><surname>Icardi</surname><given-names>L</given-names></name>, <name><surname>Mori</surname><given-names>R</given-names></name>, <name><surname>Gesellchen</surname><given-names>V</given-names></name>, <name><surname>Eyckerman</surname><given-names>S</given-names></name>, <name><surname>De Cauwer</surname><given-names>L</given-names></name>, <etal>et al</etal> (<year>2012</year>) <article-title>The Sin3a repressor complex is a master regulator of STAT transcriptional activity</article-title>. <source>Proceedings of the National Academy of Sciences of the United States of America</source><volume>109</volume>: <fpage>12058</fpage>–<lpage>12063</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1073/pnas.1206458109">10.1073/pnas.1206458109</ext-link></comment><pub-id pub-id-type="pmid">22783022</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref060"><label>60</label><mixed-citation publication-type="journal"><name><surname>Ivashkiv</surname><given-names>LB</given-names></name>, <name><surname>Donlin</surname><given-names>LT</given-names></name> (<year>2014</year>) <article-title>Regulation of type I interferon responses</article-title>. <source>Nat Rev Immunol</source><volume>14</volume>: <fpage>36</fpage>–<lpage>49</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1038/nri3581">10.1038/nri3581</ext-link></comment><pub-id pub-id-type="pmid">24362405</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref061"><label>61</label><mixed-citation publication-type="book"><name><surname>Heim</surname><given-names>MH</given-names></name> (<year>2015</year>) <chapter-title>Interferon signaling</chapter-title> In: <name><surname>Jean-François Dufour</surname><given-names>P-AC</given-names></name>, editor. <source>Signaling pathways in liver diseases</source>. <edition>3rd ed</edition>: <publisher-name>Wiley Blackwell</publisher-name> pp. <fpage>214</fpage>–<lpage>225</lpage>.</mixed-citation></ref><ref id="ppat.1006839.ref062"><label>62</label><mixed-citation publication-type="journal"><name><surname>Karin</surname><given-names>M</given-names></name>, <name><surname>Clevers</surname><given-names>H</given-names></name> (<year>2016</year>) <article-title>Reparative inflammation takes charge of tissue regeneration</article-title>. <source>Nature</source><volume>529</volume>: <fpage>307</fpage>–<lpage>315</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1038/nature17039">10.1038/nature17039</ext-link></comment><pub-id pub-id-type="pmid">26791721</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref063"><label>63</label><mixed-citation publication-type="journal"><name><surname>Michalopoulos</surname><given-names>GK</given-names></name> (<year>2013</year>) <article-title>Principles of liver regeneration and growth homeostasis</article-title>. <source>Comprehensive Physiology</source><volume>3</volume>: <fpage>485</fpage>–<lpage>513</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1002/cphy.c120014">10.1002/cphy.c120014</ext-link></comment><pub-id pub-id-type="pmid">23720294</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref064"><label>64</label><mixed-citation publication-type="journal"><name><surname>Michalopoulos</surname><given-names>GK</given-names></name> (<year>2014</year>) <article-title>Advances in liver regeneration</article-title>. <source>Expert review of gastroenterology & hepatology</source><volume>8</volume>: <fpage>897</fpage>–<lpage>907</lpage>.<pub-id pub-id-type="pmid">24964729</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref065"><label>65</label><mixed-citation publication-type="journal"><name><surname>Robinson</surname><given-names>MW</given-names></name>, <name><surname>Harmon</surname><given-names>C</given-names></name>, <name><surname>O'Farrelly</surname><given-names>C</given-names></name> (<year>2016</year>) <article-title>Liver immunology and its role in inflammation and homeostasis</article-title>. <source>Cellular & molecular immunology</source><volume>13</volume>: <fpage>267</fpage>–<lpage>276</lpage>.<pub-id pub-id-type="pmid">27063467</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref066"><label>66</label><mixed-citation publication-type="journal"><name><surname>Selzner</surname><given-names>N</given-names></name>, <name><surname>Selzner</surname><given-names>M</given-names></name>, <name><surname>Odermatt</surname><given-names>B</given-names></name>, <name><surname>Tian</surname><given-names>Y</given-names></name>, <name><surname>Van Rooijen</surname><given-names>N</given-names></name>, <etal>et al</etal> (<year>2003</year>) <article-title>ICAM-1 triggers liver regeneration through leukocyte recruitment and Kupffer cell-dependent release of TNF-alpha/IL-6 in mice</article-title>. <source>Gastroenterology</source><volume>124</volume>: <fpage>692</fpage>–<lpage>700</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1053/gast.2003.50098">10.1053/gast.2003.50098</ext-link></comment><pub-id pub-id-type="pmid">12612908</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref067"><label>67</label><mixed-citation publication-type="journal"><name><surname>Michalopoulos</surname><given-names>GK</given-names></name> (<year>2007</year>) <article-title>Liver regeneration</article-title>. <source>Journal of cellular physiology</source><volume>213</volume>: <fpage>286</fpage>–<lpage>300</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1002/jcp.21172">10.1002/jcp.21172</ext-link></comment><pub-id pub-id-type="pmid">17559071</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref068"><label>68</label><mixed-citation publication-type="journal"><name><surname>Yu</surname><given-names>H</given-names></name>, <name><surname>Lee</surname><given-names>H</given-names></name>, <name><surname>Herrmann</surname><given-names>A</given-names></name>, <name><surname>Buettner</surname><given-names>R</given-names></name>, <name><surname>Jove</surname><given-names>R</given-names></name> (<year>2014</year>) <article-title>Revisiting STAT3 signalling in cancer: new and unexpected biological functions</article-title>. <source>Nature reviews Cancer</source><volume>14</volume>: <fpage>736</fpage>–<lpage>746</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1038/nrc3818">10.1038/nrc3818</ext-link></comment><pub-id pub-id-type="pmid">25342631</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref069"><label>69</label><mixed-citation publication-type="journal"><name><surname>Holland</surname><given-names>SM</given-names></name>, <name><surname>DeLeo</surname><given-names>FR</given-names></name>, <name><surname>Elloumi</surname><given-names>HZ</given-names></name>, <name><surname>Hsu</surname><given-names>AP</given-names></name>, <name><surname>Uzel</surname><given-names>G</given-names></name>, <etal>et al</etal> (<year>2007</year>) <article-title>STAT3 mutations in the hyper-IgE syndrome</article-title>. <source>The New England journal of medicine</source><volume>357</volume>: <fpage>1608</fpage>–<lpage>1619</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1056/NEJMoa073687">10.1056/NEJMoa073687</ext-link></comment><pub-id pub-id-type="pmid">17881745</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref070"><label>70</label><mixed-citation publication-type="journal"><name><surname>Siegel</surname><given-names>AM</given-names></name>, <name><surname>Heimall</surname><given-names>J</given-names></name>, <name><surname>Freeman</surname><given-names>AF</given-names></name>, <name><surname>Hsu</surname><given-names>AP</given-names></name>, <name><surname>Brittain</surname><given-names>E</given-names></name>, <etal>et al</etal> (<year>2011</year>) <article-title>A critical role for STAT3 transcription factor signaling in the development and maintenance of human T cell memory</article-title>. <source>Immunity</source><volume>35</volume>: <fpage>806</fpage>–<lpage>818</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1016/j.immuni.2011.09.016">10.1016/j.immuni.2011.09.016</ext-link></comment><pub-id pub-id-type="pmid">22118528</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref071"><label>71</label><mixed-citation publication-type="journal"><name><surname>Waris</surname><given-names>G</given-names></name>, <name><surname>Siddiqui</surname><given-names>A</given-names></name> (<year>2002</year>) <article-title>Interaction between STAT-3 and HNF-3 leads to the activation of liver-specific hepatitis B virus enhancer 1 function</article-title>. <source>J Virol</source><volume>76</volume>: <fpage>2721</fpage>–<lpage>2729</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/JVI.76.6.2721-2729.2002">10.1128/JVI.76.6.2721-2729.2002</ext-link></comment><pub-id pub-id-type="pmid">11861839</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref072"><label>72</label><mixed-citation publication-type="journal"><name><surname>Lee</surname><given-names>YH</given-names></name>, <name><surname>Yun</surname><given-names>Y</given-names></name> (<year>1998</year>) <article-title>HBx protein of hepatitis B virus activates Jak1-STAT signaling</article-title>. <source>J Biol Chem</source><volume>273</volume>: <fpage>25510</fpage>–<lpage>25515</lpage>. <pub-id pub-id-type="pmid">9738022</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref073"><label>73</label><mixed-citation publication-type="journal"><name><surname>Yuan</surname><given-names>K</given-names></name>, <name><surname>Lei</surname><given-names>Y</given-names></name>, <name><surname>Chen</surname><given-names>HN</given-names></name>, <name><surname>Chen</surname><given-names>Y</given-names></name>, <name><surname>Zhang</surname><given-names>T</given-names></name>, <etal>et al</etal> (<year>2016</year>) <article-title>HBV-induced ROS accumulation promotes hepatocarcinogenesis through Snail-mediated epigenetic silencing of SOCS3</article-title>. <source>Cell Death Differ</source><volume>23</volume>: <fpage>616</fpage>–<lpage>627</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1038/cdd.2015.129">10.1038/cdd.2015.129</ext-link></comment><pub-id pub-id-type="pmid">26794444</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref074"><label>74</label><mixed-citation publication-type="journal"><name><surname>McCartney</surname><given-names>EM</given-names></name>, <name><surname>Helbig</surname><given-names>KJ</given-names></name>, <name><surname>Narayana</surname><given-names>SK</given-names></name>, <name><surname>Eyre</surname><given-names>NS</given-names></name>, <name><surname>Aloia</surname><given-names>AL</given-names></name>, <etal>et al</etal> (<year>2013</year>) <article-title>Signal transducer and activator of transcription 3 is a proviral host factor for hepatitis C virus</article-title>. <source>Hepatology</source><volume>58</volume>: <fpage>1558</fpage>–<lpage>1568</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1002/hep.26496">10.1002/hep.26496</ext-link></comment><pub-id pub-id-type="pmid">23703790</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref075"><label>75</label><mixed-citation publication-type="journal"><name><surname>Yoshida</surname><given-names>T</given-names></name>, <name><surname>Hanada</surname><given-names>T</given-names></name>, <name><surname>Tokuhisa</surname><given-names>T</given-names></name>, <name><surname>Kosai</surname><given-names>K</given-names></name>, <name><surname>Sata</surname><given-names>M</given-names></name>, <etal>et al</etal> (<year>2002</year>) <article-title>Activation of STAT3 by the hepatitis C virus core protein leads to cellular transformation</article-title>. <source>The Journal of experimental medicine</source><volume>196</volume>: <fpage>641</fpage>–<lpage>653</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1084/jem.20012127">10.1084/jem.20012127</ext-link></comment><pub-id pub-id-type="pmid">12208879</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref076"><label>76</label><mixed-citation publication-type="journal"><name><surname>Gong</surname><given-names>G</given-names></name>, <name><surname>Waris</surname><given-names>G</given-names></name>, <name><surname>Tanveer</surname><given-names>R</given-names></name>, <name><surname>Siddiqui</surname><given-names>A</given-names></name> (<year>2001</year>) <article-title>Human hepatitis C virus NS5A protein alters intracellular calcium levels, induces oxidative stress, and activates STAT-3 and NF-kappa B</article-title>. <source>Proc Natl Acad Sci U S A</source><volume>98</volume>: <fpage>9599</fpage>–<lpage>9604</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1073/pnas.171311298">10.1073/pnas.171311298</ext-link></comment><pub-id pub-id-type="pmid">11481452</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref077"><label>77</label><mixed-citation publication-type="journal"><name><surname>Pinkham</surname><given-names>C</given-names></name>, <name><surname>An</surname><given-names>S</given-names></name>, <name><surname>Lundberg</surname><given-names>L</given-names></name>, <name><surname>Bansal</surname><given-names>N</given-names></name>, <name><surname>Benedict</surname><given-names>A</given-names></name>, <etal>et al</etal> (<year>2016</year>) <article-title>The role of signal transducer and activator of transcription 3 in Rift Valley fever virus infection</article-title>. <source>Virology</source><volume>496</volume>: <fpage>175</fpage>–<lpage>185</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1016/j.virol.2016.06.004">10.1016/j.virol.2016.06.004</ext-link></comment><pub-id pub-id-type="pmid">27318793</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref078"><label>78</label><mixed-citation publication-type="journal"><name><surname>Slinger</surname><given-names>E</given-names></name>, <name><surname>Maussang</surname><given-names>D</given-names></name>, <name><surname>Schreiber</surname><given-names>A</given-names></name>, <name><surname>Siderius</surname><given-names>M</given-names></name>, <name><surname>Rahbar</surname><given-names>A</given-names></name>, <etal>et al</etal> (<year>2010</year>) <article-title>HCMV-encoded chemokine receptor US28 mediates proliferative signaling through the IL-6-STAT3 axis</article-title>. <source>Sci Signal</source><volume>3</volume>: <fpage>ra58</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1126/scisignal.2001180">10.1126/scisignal.2001180</ext-link></comment><pub-id pub-id-type="pmid">20682912</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref079"><label>79</label><mixed-citation publication-type="journal"><name><surname>Lepiller</surname><given-names>Q</given-names></name>, <name><surname>Abbas</surname><given-names>W</given-names></name>, <name><surname>Kumar</surname><given-names>A</given-names></name>, <name><surname>Tripathy</surname><given-names>MK</given-names></name>, <name><surname>Herbein</surname><given-names>G</given-names></name> (<year>2013</year>) <article-title>HCMV activates the IL-6-JAK-STAT3 axis in HepG2 cells and primary human hepatocytes</article-title>. <source>PLoS ONE</source><volume>8</volume>: <fpage>e59591</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1371/journal.pone.0059591">10.1371/journal.pone.0059591</ext-link></comment><pub-id pub-id-type="pmid">23555719</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref080"><label>80</label><mixed-citation publication-type="journal"><name><surname>Kotenko</surname><given-names>SV</given-names></name>, <name><surname>Saccani</surname><given-names>S</given-names></name>, <name><surname>Izotova</surname><given-names>LS</given-names></name>, <name><surname>Mirochnitchenko</surname><given-names>OV</given-names></name>, <name><surname>Pestka</surname><given-names>S</given-names></name> (<year>2000</year>) <article-title>Human cytomegalovirus harbors its own unique IL-10 homolog (cmvIL-10)</article-title>. <source>Proc Natl Acad Sci U S A</source><volume>97</volume>: <fpage>1695</fpage>–<lpage>1700</lpage>. <pub-id pub-id-type="pmid">10677520</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref081"><label>81</label><mixed-citation publication-type="journal"><name><surname>Raftery</surname><given-names>MJ</given-names></name>, <name><surname>Wieland</surname><given-names>D</given-names></name>, <name><surname>Gronewald</surname><given-names>S</given-names></name>, <name><surname>Kraus</surname><given-names>AA</given-names></name>, <name><surname>Giese</surname><given-names>T</given-names></name>, <etal>et al</etal> (<year>2004</year>) <article-title>Shaping phenotype, function, and survival of dendritic cells by cytomegalovirus-encoded IL-10</article-title>. <source>J Immunol</source><volume>173</volume>: <fpage>3383</fpage>–<lpage>3391</lpage>. <pub-id pub-id-type="pmid">15322202</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref082"><label>82</label><mixed-citation publication-type="journal"><name><surname>Spencer</surname><given-names>JV</given-names></name> (<year>2007</year>) <article-title>The cytomegalovirus homolog of interleukin-10 requires phosphatidylinositol 3-kinase activity for inhibition of cytokine synthesis in monocytes</article-title>. <source>J Virol</source><volume>81</volume>: <fpage>2083</fpage>–<lpage>2086</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/JVI.01655-06">10.1128/JVI.01655-06</ext-link></comment><pub-id pub-id-type="pmid">17121792</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref083"><label>83</label><mixed-citation publication-type="journal"><name><surname>Chen</surname><given-names>H</given-names></name>, <name><surname>Hutt-Fletcher</surname><given-names>L</given-names></name>, <name><surname>Cao</surname><given-names>L</given-names></name>, <name><surname>Hayward</surname><given-names>SD</given-names></name> (<year>2003</year>) <article-title>A positive autoregulatory loop of LMP1 expression and STAT activation in epithelial cells latently infected with Epstein-Barr virus</article-title>. <source>J Virol</source><volume>77</volume>: <fpage>4139</fpage>–<lpage>4148</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/JVI.77.7.4139-4148.2003">10.1128/JVI.77.7.4139-4148.2003</ext-link></comment><pub-id pub-id-type="pmid">12634372</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref084"><label>84</label><mixed-citation publication-type="journal"><name><surname>Kung</surname><given-names>CP</given-names></name>, <name><surname>Meckes</surname><given-names>DG</given-names><suffix>Jr.</suffix></name>, <name><surname>Raab-Traub</surname><given-names>N</given-names></name> (<year>2011</year>) <article-title>Epstein-Barr virus LMP1 activates EGFR, STAT3, and ERK through effects on PKCdelta</article-title>. <source>J Virol</source><volume>85</volume>: <fpage>4399</fpage>–<lpage>4408</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/JVI.01703-10">10.1128/JVI.01703-10</ext-link></comment><pub-id pub-id-type="pmid">21307189</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref085"><label>85</label><mixed-citation publication-type="journal"><name><surname>Muromoto</surname><given-names>R</given-names></name>, <name><surname>Ikeda</surname><given-names>O</given-names></name>, <name><surname>Okabe</surname><given-names>K</given-names></name>, <name><surname>Togi</surname><given-names>S</given-names></name>, <name><surname>Kamitani</surname><given-names>S</given-names></name>, <etal>et al</etal> (<year>2009</year>) <article-title>Epstein-Barr virus-derived EBNA2 regulates STAT3 activation</article-title>. <source>Biochem Biophys Res Commun</source><volume>378</volume>: <fpage>439</fpage>–<lpage>443</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1016/j.bbrc.2008.11.053">10.1016/j.bbrc.2008.11.053</ext-link></comment><pub-id pub-id-type="pmid">19032945</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref086"><label>86</label><mixed-citation publication-type="journal"><name><surname>Moore</surname><given-names>KW</given-names></name>, <name><surname>Vieira</surname><given-names>P</given-names></name>, <name><surname>Fiorentino</surname><given-names>DF</given-names></name>, <name><surname>Trounstine</surname><given-names>ML</given-names></name>, <name><surname>Khan</surname><given-names>TA</given-names></name>, <etal>et al</etal> (<year>1990</year>) <article-title>Homology of cytokine synthesis inhibitory factor (IL-10) to the Epstein-Barr virus gene BCRFI</article-title>. <source>Science</source><volume>248</volume>: <fpage>1230</fpage>–<lpage>1234</lpage>. <pub-id pub-id-type="pmid">2161559</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref087"><label>87</label><mixed-citation publication-type="journal"><name><surname>Ding</surname><given-names>Y</given-names></name>, <name><surname>Qin</surname><given-names>L</given-names></name>, <name><surname>Kotenko</surname><given-names>SV</given-names></name>, <name><surname>Pestka</surname><given-names>S</given-names></name>, <name><surname>Bromberg</surname><given-names>JS</given-names></name> (<year>2000</year>) <article-title>A single amino acid determines the immunostimulatory activity of interleukin 10</article-title>. <source>J Exp Med</source><volume>191</volume>: <fpage>213</fpage>–<lpage>224</lpage>. <pub-id pub-id-type="pmid">10637267</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref088"><label>88</label><mixed-citation publication-type="journal"><name><surname>Wan</surname><given-names>X</given-names></name>, <name><surname>Wang</surname><given-names>H</given-names></name>, <name><surname>Nicholas</surname><given-names>J</given-names></name> (<year>1999</year>) <article-title>Human herpesvirus 8 interleukin-6 (vIL-6) signals through gp130 but has structural and receptor-binding properties distinct from those of human IL-6</article-title>. <source>J Virol</source><volume>73</volume>: <fpage>8268</fpage>–<lpage>8278</lpage>. <pub-id pub-id-type="pmid">10482577</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref089"><label>89</label><mixed-citation publication-type="journal"><name><surname>Santarelli</surname><given-names>R</given-names></name>, <name><surname>Gonnella</surname><given-names>R</given-names></name>, <name><surname>Di Giovenale</surname><given-names>G</given-names></name>, <name><surname>Cuomo</surname><given-names>L</given-names></name>, <name><surname>Capobianchi</surname><given-names>A</given-names></name>, <etal>et al</etal> (<year>2014</year>) <article-title>STAT3 activation by KSHV correlates with IL-10, IL-6 and IL-23 release and an autophagic block in dendritic cells</article-title>. <source>Sci Rep</source><volume>4</volume>: <fpage>4241</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1038/srep04241">10.1038/srep04241</ext-link></comment><pub-id pub-id-type="pmid">24577500</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref090"><label>90</label><mixed-citation publication-type="journal"><name><surname>Sen</surname><given-names>N</given-names></name>, <name><surname>Che</surname><given-names>X</given-names></name>, <name><surname>Rajamani</surname><given-names>J</given-names></name>, <name><surname>Zerboni</surname><given-names>L</given-names></name>, <name><surname>Sung</surname><given-names>P</given-names></name>, <etal>et al</etal> (<year>2012</year>) <article-title>Signal transducer and activator of transcription 3 (STAT3) and survivin induction by varicella-zoster virus promote replication and skin pathogenesis</article-title>. <source>Proc Natl Acad Sci U S A</source><volume>109</volume>: <fpage>600</fpage>–<lpage>605</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1073/pnas.1114232109">10.1073/pnas.1114232109</ext-link></comment><pub-id pub-id-type="pmid">22190485</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref091"><label>91</label><mixed-citation publication-type="journal"><name><surname>Docherty</surname><given-names>JJ</given-names></name>, <name><surname>Sweet</surname><given-names>TJ</given-names></name>, <name><surname>Bailey</surname><given-names>E</given-names></name>, <name><surname>Faith</surname><given-names>SA</given-names></name>, <name><surname>Booth</surname><given-names>T</given-names></name> (<year>2006</year>) <article-title>Resveratrol inhibition of varicella-zoster virus replication In vitro</article-title>. <source>Antiviral Res</source><volume>72</volume>: <fpage>171</fpage>–<lpage>177</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1016/j.antiviral.2006.07.004">10.1016/j.antiviral.2006.07.004</ext-link></comment><pub-id pub-id-type="pmid">16899306</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref092"><label>92</label><mixed-citation publication-type="journal"><name><surname>Zhu</surname><given-names>S</given-names></name>, <name><surname>Luo</surname><given-names>H</given-names></name>, <name><surname>Liu</surname><given-names>H</given-names></name>, <name><surname>Ha</surname><given-names>Y</given-names></name>, <name><surname>Mays</surname><given-names>ER</given-names></name>, <etal>et al</etal> (<year>2017</year>) <article-title>p38MAPK plays a critical role in induction of a pro-inflammatory phenotype of retinal Muller cells following Zika virus infection</article-title>. <source>Antiviral Res</source><volume>145</volume>: <fpage>70</fpage>–<lpage>81</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1016/j.antiviral.2017.07.012">10.1016/j.antiviral.2017.07.012</ext-link></comment><pub-id pub-id-type="pmid">28739278</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref093"><label>93</label><mixed-citation publication-type="journal"><name><surname>Aid</surname><given-names>M</given-names></name>, <name><surname>Abbink</surname><given-names>P</given-names></name>, <name><surname>Larocca</surname><given-names>RA</given-names></name>, <name><surname>Boyd</surname><given-names>M</given-names></name>, <name><surname>Nityanandam</surname><given-names>R</given-names></name>, <etal>et al</etal> (<year>2017</year>) <article-title>Zika Virus Persistence in the Central Nervous System and Lymph Nodes of Rhesus Monkeys</article-title>. <source>Cell</source><volume>169</volume>: <fpage>610</fpage>–<lpage>620</lpage> e614. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1016/j.cell.2017.04.008">10.1016/j.cell.2017.04.008</ext-link></comment><pub-id pub-id-type="pmid">28457610</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref094"><label>94</label><mixed-citation publication-type="journal"><name><surname>Ulane</surname><given-names>CM</given-names></name>, <name><surname>Rodriguez</surname><given-names>JJ</given-names></name>, <name><surname>Parisien</surname><given-names>JP</given-names></name>, <name><surname>Horvath</surname><given-names>CM</given-names></name> (<year>2003</year>) <article-title>STAT3 ubiquitylation and degradation by mumps virus suppress cytokine and oncogene signaling</article-title>. <source>J Virol</source><volume>77</volume>: <fpage>6385</fpage>–<lpage>6393</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/JVI.77.11.6385-6393.2003">10.1128/JVI.77.11.6385-6393.2003</ext-link></comment><pub-id pub-id-type="pmid">12743296</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref095"><label>95</label><mixed-citation publication-type="journal"><name><surname>Palosaari</surname><given-names>H</given-names></name>, <name><surname>Parisien</surname><given-names>JP</given-names></name>, <name><surname>Rodriguez</surname><given-names>JJ</given-names></name>, <name><surname>Ulane</surname><given-names>CM</given-names></name>, <name><surname>Horvath</surname><given-names>CM</given-names></name> (<year>2003</year>) <article-title>STAT protein interference and suppression of cytokine signal transduction by measles virus V protein</article-title>. <source>J Virol</source><volume>77</volume>: <fpage>7635</fpage>–<lpage>7644</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/JVI.77.13.7635-7644.2003">10.1128/JVI.77.13.7635-7644.2003</ext-link></comment><pub-id pub-id-type="pmid">12805463</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref096"><label>96</label><mixed-citation publication-type="journal"><name><surname>Hui</surname><given-names>KP</given-names></name>, <name><surname>Li</surname><given-names>HS</given-names></name>, <name><surname>Cheung</surname><given-names>MC</given-names></name>, <name><surname>Chan</surname><given-names>RW</given-names></name>, <name><surname>Yuen</surname><given-names>KM</given-names></name>, <etal>et al</etal> (<year>2016</year>) <article-title>Highly pathogenic avian influenza H5N1 virus delays apoptotic responses via activation of STAT3</article-title>. <source>Sci Rep</source><volume>6</volume>: <fpage>28593</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1038/srep28593">10.1038/srep28593</ext-link></comment><pub-id pub-id-type="pmid">27344974</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref097"><label>97</label><mixed-citation publication-type="journal"><name><surname>Jia</surname><given-names>D</given-names></name>, <name><surname>Rahbar</surname><given-names>R</given-names></name>, <name><surname>Chan</surname><given-names>RW</given-names></name>, <name><surname>Lee</surname><given-names>SM</given-names></name>, <name><surname>Chan</surname><given-names>MC</given-names></name>, <etal>et al</etal> (<year>2010</year>) <article-title>Influenza virus non-structural protein 1 (NS1) disrupts interferon signaling</article-title>. <source>PLoS ONE</source><volume>5</volume>: <fpage>e13927</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1371/journal.pone.0013927">10.1371/journal.pone.0013927</ext-link></comment><pub-id pub-id-type="pmid">21085662</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref098"><label>98</label><mixed-citation publication-type="journal"><name><surname>Chandra</surname><given-names>V</given-names></name>, <name><surname>Kar-Roy</surname><given-names>A</given-names></name>, <name><surname>Kumari</surname><given-names>S</given-names></name>, <name><surname>Mayor</surname><given-names>S</given-names></name>, <name><surname>Jameel</surname><given-names>S</given-names></name> (<year>2008</year>) <article-title>The hepatitis E virus ORF3 protein modulates epidermal growth factor receptor trafficking, STAT3 translocation, and the acute-phase response</article-title>. <source>J Virol</source><volume>82</volume>: <fpage>7100</fpage>–<lpage>7110</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/JVI.00403-08">10.1128/JVI.00403-08</ext-link></comment><pub-id pub-id-type="pmid">18448545</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref099"><label>99</label><mixed-citation publication-type="journal"><name><surname>Lieu</surname><given-names>KG</given-names></name>, <name><surname>Brice</surname><given-names>A</given-names></name>, <name><surname>Wiltzer</surname><given-names>L</given-names></name>, <name><surname>Hirst</surname><given-names>B</given-names></name>, <name><surname>Jans</surname><given-names>DA</given-names></name>, <etal>et al</etal> (<year>2013</year>) <article-title>The rabies virus interferon antagonist P protein interacts with activated STAT3 and inhibits Gp130 receptor signaling</article-title>. <source>J Virol</source><volume>87</volume>: <fpage>8261</fpage>–<lpage>8265</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/JVI.00989-13">10.1128/JVI.00989-13</ext-link></comment><pub-id pub-id-type="pmid">23698294</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref100"><label>100</label><mixed-citation publication-type="journal"><name><surname>Mitzel</surname><given-names>DN</given-names></name>, <name><surname>Jaramillo</surname><given-names>RJ</given-names></name>, <name><surname>Stout-Delgado</surname><given-names>H</given-names></name>, <name><surname>Senft</surname><given-names>AP</given-names></name>, <name><surname>Harrod</surname><given-names>KS</given-names></name> (<year>2014</year>) <article-title>Human metapneumovirus inhibits the IL-6-induced JAK/STAT3 signalling cascade in airway epithelium</article-title>. <source>J Gen Virol</source><volume>95</volume>: <fpage>26</fpage>–<lpage>37</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1099/vir.0.055632-0">10.1099/vir.0.055632-0</ext-link></comment><pub-id pub-id-type="pmid">24114793</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref101"><label>101</label><mixed-citation publication-type="journal"><name><surname>Reitsma</surname><given-names>JM</given-names></name>, <name><surname>Sato</surname><given-names>H</given-names></name>, <name><surname>Nevels</surname><given-names>M</given-names></name>, <name><surname>Terhune</surname><given-names>SS</given-names></name>, <name><surname>Paulus</surname><given-names>C</given-names></name> (<year>2013</year>) <article-title>Human cytomegalovirus IE1 protein disrupts interleukin-6 signaling by sequestering STAT3 in the nucleus</article-title>. <source>J Virol</source><volume>87</volume>: <fpage>10763</fpage>–<lpage>10776</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/JVI.01197-13">10.1128/JVI.01197-13</ext-link></comment><pub-id pub-id-type="pmid">23903834</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref102"><label>102</label><mixed-citation publication-type="journal"><name><surname>Ramalingam</surname><given-names>D</given-names></name>, <name><surname>Ziegelbauer</surname><given-names>JM</given-names></name> (<year>2017</year>) <article-title>Viral microRNAs Target a Gene Network, Inhibit STAT Activation, and Suppress Interferon Responses</article-title>. <source>Sci Rep</source><volume>7</volume>: <fpage>40813</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1038/srep40813">10.1038/srep40813</ext-link></comment><pub-id pub-id-type="pmid">28102325</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref103"><label>103</label><mixed-citation publication-type="journal"><name><surname>Li</surname><given-names>L</given-names></name>, <name><surname>Chong</surname><given-names>HC</given-names></name>, <name><surname>Ng</surname><given-names>SY</given-names></name>, <name><surname>Kwok</surname><given-names>KW</given-names></name>, <name><surname>Teo</surname><given-names>Z</given-names></name>, <etal>et al</etal> (<year>2015</year>) <article-title>Angiopoietin-like 4 Increases Pulmonary Tissue Leakiness and Damage during Influenza Pneumonia</article-title>. <source>Cell Rep</source>.</mixed-citation></ref><ref id="ppat.1006839.ref104"><label>104</label><mixed-citation publication-type="journal"><name><surname>Kane</surname><given-names>M</given-names></name>, <name><surname>Golovkina</surname><given-names>T</given-names></name> (<year>2010</year>) <article-title>Common threads in persistent viral infections</article-title>. <source>J Virol</source><volume>84</volume>: <fpage>4116</fpage>–<lpage>4123</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/JVI.01905-09">10.1128/JVI.01905-09</ext-link></comment><pub-id pub-id-type="pmid">19955304</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref105"><label>105</label><mixed-citation publication-type="journal"><name><surname>Danthi</surname><given-names>P</given-names></name> (<year>2016</year>) <article-title>Viruses and the Diversity of Cell Death</article-title>. <source>Annu Rev Virol</source><volume>3</volume>: <fpage>533</fpage>–<lpage>553</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1146/annurev-virology-110615-042435">10.1146/annurev-virology-110615-042435</ext-link></comment><pub-id pub-id-type="pmid">27501259</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref106"><label>106</label><mixed-citation publication-type="journal"><name><surname>Yu</surname><given-names>H</given-names></name>, <name><surname>Kortylewski</surname><given-names>M</given-names></name>, <name><surname>Pardoll</surname><given-names>D</given-names></name> (<year>2007</year>) <article-title>Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment</article-title>. <source>Nat Rev Immunol</source><volume>7</volume>: <fpage>41</fpage>–<lpage>51</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1038/nri1995">10.1038/nri1995</ext-link></comment><pub-id pub-id-type="pmid">17186030</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref107"><label>107</label><mixed-citation publication-type="journal"><name><surname>Koganti</surname><given-names>S</given-names></name>, <name><surname>Clark</surname><given-names>C</given-names></name>, <name><surname>Zhi</surname><given-names>J</given-names></name>, <name><surname>Li</surname><given-names>X</given-names></name>, <name><surname>Chen</surname><given-names>EI</given-names></name>, <etal>et al</etal> (<year>2015</year>) <article-title>Cellular STAT3 functions via PCBP2 to restrain Epstein-Barr Virus lytic activation in B lymphocytes</article-title>. <source>J Virol</source><volume>89</volume>: <fpage>5002</fpage>–<lpage>5011</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/JVI.00121-15">10.1128/JVI.00121-15</ext-link></comment><pub-id pub-id-type="pmid">25717101</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref108"><label>108</label><mixed-citation publication-type="journal"><name><surname>King</surname><given-names>CA</given-names></name>, <name><surname>Li</surname><given-names>X</given-names></name>, <name><surname>Barbachano-Guerrero</surname><given-names>A</given-names></name>, <name><surname>Bhaduri-McIntosh</surname><given-names>S</given-names></name> (<year>2015</year>) <article-title>STAT3 Regulates Lytic Activation of Kaposi's Sarcoma-Associated Herpesvirus</article-title>. <source>J Virol</source><volume>89</volume>: <fpage>11347</fpage>–<lpage>11355</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/JVI.02008-15">10.1128/JVI.02008-15</ext-link></comment><pub-id pub-id-type="pmid">26339061</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref109"><label>109</label><mixed-citation publication-type="journal"><name><surname>Zhang</surname><given-names>D</given-names></name>, <name><surname>Sun</surname><given-names>M</given-names></name>, <name><surname>Samols</surname><given-names>D</given-names></name>, <name><surname>Kushner</surname><given-names>I</given-names></name> (<year>1996</year>) <article-title>STAT3 participates in transcriptional activation of the C-reactive protein gene by interleukin-6</article-title>. <source>J Biol Chem</source><volume>271</volume>: <fpage>9503</fpage>–<lpage>9509</lpage>. <pub-id pub-id-type="pmid">8621622</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref110"><label>110</label><mixed-citation publication-type="journal"><name><surname>Lv</surname><given-names>D</given-names></name>, <name><surname>Zhang</surname><given-names>Y</given-names></name>, <name><surname>Kim</surname><given-names>HJ</given-names></name>, <name><surname>Zhang</surname><given-names>L</given-names></name>, <name><surname>Ma</surname><given-names>X</given-names></name> (<year>2013</year>) <article-title>CCL5 as a potential immunotherapeutic target in triple-negative breast cancer</article-title>. <source>Cell Mol Immunol</source><volume>10</volume>: <fpage>303</fpage>–<lpage>310</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1038/cmi.2012.69">10.1038/cmi.2012.69</ext-link></comment><pub-id pub-id-type="pmid">23376885</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref111"><label>111</label><mixed-citation publication-type="journal"><name><surname>Halary</surname><given-names>F</given-names></name>, <name><surname>Amara</surname><given-names>A</given-names></name>, <name><surname>Lortat-Jacob</surname><given-names>H</given-names></name>, <name><surname>Messerle</surname><given-names>M</given-names></name>, <name><surname>Delaunay</surname><given-names>T</given-names></name>, <etal>et al</etal> (<year>2002</year>) <article-title>Human cytomegalovirus binding to DC-SIGN is required for dendritic cell infection and target cell trans-infection</article-title>. <source>Immunity</source><volume>17</volume>: <fpage>653</fpage>–<lpage>664</lpage>. <pub-id pub-id-type="pmid">12433371</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref112"><label>112</label><mixed-citation publication-type="journal"><name><surname>Shin</surname><given-names>EC</given-names></name>, <name><surname>Sung</surname><given-names>PS</given-names></name>, <name><surname>Park</surname><given-names>SH</given-names></name> (<year>2016</year>) <article-title>Immune responses and immunopathology in acute and chronic viral hepatitis</article-title>. <source>Nat Rev Immunol</source><volume>16</volume>: <fpage>509</fpage>–<lpage>523</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1038/nri.2016.69">10.1038/nri.2016.69</ext-link></comment><pub-id pub-id-type="pmid">27374637</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref113"><label>113</label><mixed-citation publication-type="journal"><name><surname>Ren</surname><given-names>JP</given-names></name>, <name><surname>Wang</surname><given-names>L</given-names></name>, <name><surname>Zhao</surname><given-names>J</given-names></name>, <name><surname>Ning</surname><given-names>SB</given-names></name>, <name><surname>El Gazzar</surname><given-names>M</given-names></name>, <etal>et al</etal> (<year>2017</year>) <article-title>Decline of miR-124 in myeloid cells promotes regulatory T-cell development in hepatitis C virus infection</article-title>. <source>Immunology</source><volume>150</volume>: <fpage>213</fpage>–<lpage>220</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1111/imm.12680">10.1111/imm.12680</ext-link></comment><pub-id pub-id-type="pmid">27753084</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref114"><label>114</label><mixed-citation publication-type="journal"><name><surname>Zhai</surname><given-names>N</given-names></name>, <name><surname>Li</surname><given-names>H</given-names></name>, <name><surname>Song</surname><given-names>H</given-names></name>, <name><surname>Yang</surname><given-names>Y</given-names></name>, <name><surname>Cui</surname><given-names>A</given-names></name>, <etal>et al</etal> (<year>2017</year>) <article-title>Hepatitis C Virus Induces MDSCs-Like Monocytes through TLR2/PI3K/AKT/STAT3 Signaling</article-title>. <source>PLoS ONE</source><volume>12</volume>: <fpage>e0170516</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1371/journal.pone.0170516">10.1371/journal.pone.0170516</ext-link></comment><pub-id pub-id-type="pmid">28114346</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref115"><label>115</label><mixed-citation publication-type="journal"><name><surname>Wan</surname><given-names>S</given-names></name>, <name><surname>Kuo</surname><given-names>N</given-names></name>, <name><surname>Kryczek</surname><given-names>I</given-names></name>, <name><surname>Zou</surname><given-names>W</given-names></name>, <name><surname>Welling</surname><given-names>TH</given-names></name> (<year>2015</year>) <article-title>Myeloid cells in hepatocellular carcinoma</article-title>. <source>Hepatology</source><volume>62</volume>: <fpage>1304</fpage>–<lpage>1312</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1002/hep.27867">10.1002/hep.27867</ext-link></comment><pub-id pub-id-type="pmid">25914264</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref116"><label>116</label><mixed-citation publication-type="journal"><name><surname>Wolk</surname><given-names>B</given-names></name>, <name><surname>Buchele</surname><given-names>B</given-names></name>, <name><surname>Moradpour</surname><given-names>D</given-names></name>, <name><surname>Rice</surname><given-names>CM</given-names></name> (<year>2008</year>) <article-title>A dynamic view of hepatitis C virus replication complexes</article-title>. <source>J Virol</source><volume>82</volume>: <fpage>10519</fpage>–<lpage>10531</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/JVI.00640-08">10.1128/JVI.00640-08</ext-link></comment><pub-id pub-id-type="pmid">18715913</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref117"><label>117</label><mixed-citation publication-type="journal"><name><surname>Roohvand</surname><given-names>F</given-names></name>, <name><surname>Maillard</surname><given-names>P</given-names></name>, <name><surname>Lavergne</surname><given-names>JP</given-names></name>, <name><surname>Boulant</surname><given-names>S</given-names></name>, <name><surname>Walic</surname><given-names>M</given-names></name>, <etal>et al</etal> (<year>2009</year>) <article-title>Initiation of hepatitis C virus infection requires the dynamic microtubule network: role of the viral nucleocapsid protein</article-title>. <source>J Biol Chem</source><volume>284</volume>: <fpage>13778</fpage>–<lpage>13791</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1074/jbc.M807873200">10.1074/jbc.M807873200</ext-link></comment><pub-id pub-id-type="pmid">19269968</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref118"><label>118</label><mixed-citation publication-type="journal"><name><surname>Llovet</surname><given-names>JM</given-names></name>, <name><surname>Zucman-Rossi</surname><given-names>J</given-names></name>, <name><surname>Pikarsky</surname><given-names>E</given-names></name>, <name><surname>Sangro</surname><given-names>B</given-names></name>, <name><surname>Schwartz</surname><given-names>M</given-names></name>, <etal>et al</etal> (<year>2016</year>) <article-title>Hepatocellular carcinoma</article-title>. <source>Nat Rev Dis Primers</source><volume>2</volume>: <fpage>16018</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1038/nrdp.2016.18">10.1038/nrdp.2016.18</ext-link></comment><pub-id pub-id-type="pmid">27158749</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref119"><label>119</label><mixed-citation publication-type="journal"><name><surname>Ho</surname><given-names>Y</given-names></name>, <name><surname>Tsao</surname><given-names>SW</given-names></name>, <name><surname>Zeng</surname><given-names>M</given-names></name>, <name><surname>Lui</surname><given-names>VW</given-names></name> (<year>2013</year>) <article-title>STAT3 as a therapeutic target for Epstein-Barr virus (EBV): associated nasopharyngeal carcinoma</article-title>. <source>Cancer Lett</source><volume>330</volume>: <fpage>141</fpage>–<lpage>149</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1016/j.canlet.2012.11.052">10.1016/j.canlet.2012.11.052</ext-link></comment><pub-id pub-id-type="pmid">23220625</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref120"><label>120</label><mixed-citation publication-type="journal"><name><surname>Lui</surname><given-names>VW</given-names></name>, <name><surname>Wong</surname><given-names>EY</given-names></name>, <name><surname>Ho</surname><given-names>Y</given-names></name>, <name><surname>Hong</surname><given-names>B</given-names></name>, <name><surname>Wong</surname><given-names>SC</given-names></name>, <etal>et al</etal> (<year>2009</year>) <article-title>STAT3 activation contributes directly to Epstein-Barr virus-mediated invasiveness of nasopharyngeal cancer cells In vitro</article-title>. <source>Int J Cancer</source><volume>125</volume>: <fpage>1884</fpage>–<lpage>1893</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1002/ijc.24567">10.1002/ijc.24567</ext-link></comment><pub-id pub-id-type="pmid">19588483</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref121"><label>121</label><mixed-citation publication-type="journal"><name><surname>Kondo</surname><given-names>S</given-names></name>, <name><surname>Yoshizaki</surname><given-names>T</given-names></name>, <name><surname>Wakisaka</surname><given-names>N</given-names></name>, <name><surname>Horikawa</surname><given-names>T</given-names></name>, <name><surname>Murono</surname><given-names>S</given-names></name>, <etal>et al</etal> (<year>2007</year>) <article-title>MUC1 induced by Epstein-Barr virus latent membrane protein 1 causes dissociation of the cell-matrix interaction and cellular invasiveness via STAT signaling</article-title>. <source>J Virol</source><volume>81</volume>: <fpage>1554</fpage>–<lpage>1562</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/JVI.02222-06">10.1128/JVI.02222-06</ext-link></comment><pub-id pub-id-type="pmid">17151127</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref122"><label>122</label><mixed-citation publication-type="journal"><name><surname>Wong</surname><given-names>ALA</given-names></name>, <name><surname>Hirpara</surname><given-names>JL</given-names></name>, <name><surname>Pervaiz</surname><given-names>S</given-names></name>, <name><surname>Eu</surname><given-names>JQ</given-names></name>, <name><surname>Sethi</surname><given-names>G</given-names></name>, <etal>et al</etal> (<year>2017</year>) <article-title>Do STAT3 inhibitors have potential in the future for cancer therapy?</article-title><source>Expert Opin Investig Drugs</source><volume>26</volume>: <fpage>883</fpage>–<lpage>887</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1080/13543784.2017.1351941">10.1080/13543784.2017.1351941</ext-link></comment><pub-id pub-id-type="pmid">28714740</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref123"><label>123</label><mixed-citation publication-type="journal"><name><surname>Niu</surname><given-names>Y</given-names></name>, <name><surname>Si</surname><given-names>Y</given-names></name>, <name><surname>Li</surname><given-names>Y</given-names></name>, <name><surname>Chi</surname><given-names>X</given-names></name>, <name><surname>Li</surname><given-names>X</given-names></name>, <etal>et al</etal> (<year>2015</year>) <article-title>A novel small-molecule inhibitor of hepatitis C virus replication acts by suppressing signal transducer and activator of transcription 3</article-title>. <source>J Antimicrob Chemother</source><volume>70</volume>: <fpage>2013</fpage>–<lpage>2023</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1093/jac/dkv077">10.1093/jac/dkv077</ext-link></comment><pub-id pub-id-type="pmid">25858355</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref124"><label>124</label><mixed-citation publication-type="journal"><name><surname>Yang</surname><given-names>Y</given-names></name>, <name><surname>Zheng</surname><given-names>B</given-names></name>, <name><surname>Han</surname><given-names>Q</given-names></name>, <name><surname>Zhang</surname><given-names>C</given-names></name>, <name><surname>Tian</surname><given-names>Z</given-names></name>, <etal>et al</etal> (<year>2016</year>) <article-title>Targeting blockage of STAT3 inhibits hepatitis B virus-related hepatocellular carcinoma</article-title>. <source>Cancer Biol Ther</source><volume>17</volume>: <fpage>449</fpage>–<lpage>456</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1080/15384047.2016.1156257">10.1080/15384047.2016.1156257</ext-link></comment><pub-id pub-id-type="pmid">26934469</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref125"><label>125</label><mixed-citation publication-type="journal"><name><surname>Miklossy</surname><given-names>G</given-names></name>, <name><surname>Hilliard</surname><given-names>TS</given-names></name>, <name><surname>Turkson</surname><given-names>J</given-names></name> (<year>2013</year>) <article-title>Therapeutic modulators of STAT signalling for human diseases</article-title>. <source>Nat Rev Drug Discov</source><volume>12</volume>: <fpage>611</fpage>–<lpage>629</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1038/nrd4088">10.1038/nrd4088</ext-link></comment><pub-id pub-id-type="pmid">23903221</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref126"><label>126</label><mixed-citation publication-type="journal"><name><surname>Espinoza</surname><given-names>JL</given-names></name>, <name><surname>Takami</surname><given-names>A</given-names></name>, <name><surname>Trung</surname><given-names>LQ</given-names></name>, <name><surname>Kato</surname><given-names>S</given-names></name>, <name><surname>Nakao</surname><given-names>S</given-names></name> (<year>2012</year>) <article-title>Resveratrol prevents EBV transformation and inhibits the outgrowth of EBV-immortalized human B cells</article-title>. <source>PLoS ONE</source><volume>7</volume>: <fpage>e51306</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1371/journal.pone.0051306">10.1371/journal.pone.0051306</ext-link></comment><pub-id pub-id-type="pmid">23251493</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref127"><label>127</label><mixed-citation publication-type="journal"><name><surname>De Leo</surname><given-names>A</given-names></name>, <name><surname>Arena</surname><given-names>G</given-names></name>, <name><surname>Lacanna</surname><given-names>E</given-names></name>, <name><surname>Oliviero</surname><given-names>G</given-names></name>, <name><surname>Colavita</surname><given-names>F</given-names></name>, <etal>et al</etal> (<year>2012</year>) <article-title>Resveratrol inhibits Epstein Barr Virus lytic cycle in Burkitt's lymphoma cells by affecting multiple molecular targets</article-title>. <source>Antiviral Res</source><volume>96</volume>: <fpage>196</fpage>–<lpage>202</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1016/j.antiviral.2012.09.003">10.1016/j.antiviral.2012.09.003</ext-link></comment><pub-id pub-id-type="pmid">22985630</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref128"><label>128</label><mixed-citation publication-type="journal"><name><surname>Liu</surname><given-names>CL</given-names></name>, <name><surname>Hung</surname><given-names>HC</given-names></name>, <name><surname>Lo</surname><given-names>SC</given-names></name>, <name><surname>Chiang</surname><given-names>CH</given-names></name>, <name><surname>Chen</surname><given-names>IJ</given-names></name>, <etal>et al</etal> (<year>2016</year>) <article-title>Using mutagenesis to explore conserved residues in the RNA-binding groove of influenza A virus nucleoprotein for antiviral drug development</article-title>. <source>Sci Rep</source><volume>6</volume>: <fpage>21662</fpage><comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1038/srep21662">10.1038/srep21662</ext-link></comment><pub-id pub-id-type="pmid">26916998</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref129"><label>129</label><mixed-citation publication-type="journal"><name><surname>Kim</surname><given-names>K</given-names></name>, <name><surname>Kim</surname><given-names>KH</given-names></name>, <name><surname>Kim</surname><given-names>HY</given-names></name>, <name><surname>Cho</surname><given-names>HK</given-names></name>, <name><surname>Sakamoto</surname><given-names>N</given-names></name>, <etal>et al</etal> (<year>2010</year>) <article-title>Curcumin inhibits hepatitis C virus replication via suppressing the Akt-SREBP-1 pathway</article-title>. <source>FEBS Lett</source><volume>584</volume>: <fpage>707</fpage>–<lpage>712</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1016/j.febslet.2009.12.019">10.1016/j.febslet.2009.12.019</ext-link></comment><pub-id pub-id-type="pmid">20026048</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref130"><label>130</label><mixed-citation publication-type="journal"><name><surname>Michaelis</surname><given-names>M</given-names></name>, <name><surname>Paulus</surname><given-names>C</given-names></name>, <name><surname>Loschmann</surname><given-names>N</given-names></name>, <name><surname>Dauth</surname><given-names>S</given-names></name>, <name><surname>Stange</surname><given-names>E</given-names></name>, <etal>et al</etal> (<year>2011</year>) <article-title>The multi-targeted kinase inhibitor sorafenib inhibits human cytomegalovirus replication</article-title>. <source>Cell Mol Life Sci</source><volume>68</volume>: <fpage>1079</fpage>–<lpage>1090</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1007/s00018-010-0510-8">10.1007/s00018-010-0510-8</ext-link></comment><pub-id pub-id-type="pmid">20803231</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref131"><label>131</label><mixed-citation publication-type="journal"><name><surname>Furtek</surname><given-names>SL</given-names></name>, <name><surname>Backos</surname><given-names>DS</given-names></name>, <name><surname>Matheson</surname><given-names>CJ</given-names></name>, <name><surname>Reigan</surname><given-names>P</given-names></name> (<year>2016</year>) <article-title>Strategies and Approaches of Targeting STAT3 for Cancer Treatment</article-title>. <source>ACS Chem Biol</source><volume>11</volume>: <fpage>308</fpage>–<lpage>318</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1021/acschembio.5b00945">10.1021/acschembio.5b00945</ext-link></comment><pub-id pub-id-type="pmid">26730496</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref132"><label>132</label><mixed-citation publication-type="journal"><name><surname>Gharwan</surname><given-names>H</given-names></name>, <name><surname>Groninger</surname><given-names>H</given-names></name> (<year>2016</year>) <article-title>Kinase inhibitors and monoclonal antibodies in oncology: clinical implications</article-title>. <source>Nat Rev Clin Oncol</source><volume>13</volume>: <fpage>209</fpage>–<lpage>227</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1038/nrclinonc.2015.213">10.1038/nrclinonc.2015.213</ext-link></comment><pub-id pub-id-type="pmid">26718105</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref133"><label>133</label><mixed-citation publication-type="journal"><name><surname>Heppler</surname><given-names>LN</given-names></name>, <name><surname>Frank</surname><given-names>DA</given-names></name> (<year>2017</year>) <article-title>Targeting Oncogenic Transcription Factors: Therapeutic Implications of Endogenous STAT Inhibitors</article-title>. <source>Trends Cancer</source><volume>3</volume>: <fpage>816</fpage>–<lpage>827</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1016/j.trecan.2017.10.004">10.1016/j.trecan.2017.10.004</ext-link></comment><pub-id pub-id-type="pmid">29198438</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref134"><label>134</label><mixed-citation publication-type="journal"><name><surname>Baell</surname><given-names>J</given-names></name>, <name><surname>Walters</surname><given-names>MA</given-names></name> (<year>2014</year>) <article-title>Chemistry: Chemical con artists foil drug discovery</article-title>. <source>Nature</source><volume>513</volume>: <fpage>481</fpage>–<lpage>483</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1038/513481a">10.1038/513481a</ext-link></comment><pub-id pub-id-type="pmid">25254460</pub-id></mixed-citation></ref><ref id="ppat.1006839.ref135"><label>135</label><mixed-citation publication-type="other">Clinicaltrials.gov (2017) AZD9150 With MEDI4736 in Patients With Advanced Pancreatic, Non-Small Lung and Colorectal Cancer.</mixed-citation></ref><ref id="ppat.1006839.ref136"><label>136</label><mixed-citation publication-type="other">Clinicaltrials.gov (2017) MEDI4736 Alone and in Combination With Tremelimumab or AZD9150 in Adult Subjects With Relapsed/Refractory DLBCL.</mixed-citation></ref><ref id="ppat.1006839.ref137"><label>137</label><mixed-citation publication-type="other">Clinicaltrials.gov (2017) Study to Assess MEDI4736 With Either AZD9150 or AZD5069 in Advanced Solid Tumors & Relapsed Metastatic Squamous Cell Carcinoma of Head & Neck.</mixed-citation></ref><ref id="ppat.1006839.ref138"><label>138</label><mixed-citation publication-type="journal"><name><surname>Hubbard</surname><given-names>JM</given-names></name>, <name><surname>Grothey</surname><given-names>A</given-names></name> (<year>2017</year>) <article-title>Napabucasin: An Update on the First-in-Class Cancer Stemness Inhibitor</article-title>. <source>Drugs</source><volume>77</volume>: <fpage>1091</fpage>–<lpage>1103</lpage>. <comment>doi: <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1007/s40265-017-0759-4">10.1007/s40265-017-0759-4</ext-link></comment><pub-id pub-id-type="pmid">28573435</pub-id></mixed-citation></ref></ref-list></back></pmc></record>Pour 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