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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology</title><author><name sortKey="Channappanavar, Rudragouda" sort="Channappanavar, Rudragouda" uniqKey="Channappanavar R" first="Rudragouda" last="Channappanavar">Rudragouda Channappanavar</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Perlman, Stanley" sort="Perlman, Stanley" uniqKey="Perlman S" first="Stanley" last="Perlman">Stanley Perlman</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">28466096</idno><idno type="pmc">7079893</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079893</idno><idno type="RBID">PMC:7079893</idno><idno type="doi">10.1007/s00281-017-0629-x</idno><date when="2017">2017</date><idno type="wicri:Area/Pmc/Corpus">000534</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000534</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology</title><author><name sortKey="Channappanavar, Rudragouda" sort="Channappanavar, Rudragouda" uniqKey="Channappanavar R" first="Rudragouda" last="Channappanavar">Rudragouda Channappanavar</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Perlman, Stanley" sort="Perlman, Stanley" uniqKey="Perlman S" first="Stanley" last="Perlman">Stanley Perlman</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author></analytic><series><title level="j">Seminars in Immunopathology</title><idno type="ISSN">1863-2297</idno><idno type="eISSN">1863-2300</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">Human coronaviruses (hCoVs) can be divided into low pathogenic and highly pathogenic coronaviruses. The low pathogenic CoVs infect the upper respiratory tract and cause mild, cold-like respiratory illness. In contrast, highly pathogenic hCoVs such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) predominantly infect lower airways and cause fatal pneumonia. Severe pneumonia caused by pathogenic hCoVs is often associated with rapid virus replication, massive inflammatory cell infiltration and elevated pro-inflammatory cytokine/chemokine responses resulting in acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Recent studies in experimentally infected animal strongly suggest a crucial role for virus-induced immunopathological events in causing fatal pneumonia after hCoV infections. Here we review the current understanding of how a dysregulated immune response may cause lung immunopathology leading to deleterious clinical manifestations after pathogenic hCoV infections.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Siddell, Szj" uniqKey="Siddell S">SZJ Siddell</name></author><author><name sortKey="Snijder, Ej" uniqKey="Snijder E">EJ Snijder</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Peck, Km" uniqKey="Peck K">KM Peck</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Su, S" uniqKey="Su S">S Su</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Weiss, Sr" uniqKey="Weiss S">SR Weiss</name></author><author><name sortKey="Navas Martin, S" uniqKey="Navas Martin S">S Navas-Martin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Heugel, J" uniqKey="Heugel J">J Heugel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kuypers, J" uniqKey="Kuypers J">J Kuypers</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Drosten, C" uniqKey="Drosten C">C Drosten</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kuiken, T" uniqKey="Kuiken T">T Kuiken</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Peiris, Js" uniqKey="Peiris J">JS Peiris</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Zaki, Am" uniqKey="Zaki A">AM Zaki</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Perlman, S" uniqKey="Perlman S">S Perlman</name></author><author><name sortKey="Netland, J" uniqKey="Netland J">J Netland</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Adney, Dr" uniqKey="Adney D">DR Adney</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Alagaili, An" uniqKey="Alagaili A">AN Alagaili</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ge, Xy" uniqKey="Ge X">XY Ge</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Menachery, Vd" uniqKey="Menachery V">VD Menachery</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Arabi, Ym" uniqKey="Arabi Y">YM Arabi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Assiri, A" uniqKey="Assiri A">A Assiri</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Leong, Hn" uniqKey="Leong H">HN Leong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Saad, M" uniqKey="Saad M">M Saad</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Al Tawfiq, Ja" uniqKey="Al Tawfiq J">JA Al-Tawfiq</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zumla, A" uniqKey="Zumla A">A Zumla</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Peiris, Js" uniqKey="Peiris J">JS Peiris</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Peiris, Js" uniqKey="Peiris J">JS Peiris</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nicholls, J" uniqKey="Nicholls J">J Nicholls</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Den Brand, Jm" uniqKey="Van Den Brand J">JM van den Brand</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gu, J" uniqKey="Gu J">J Gu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nicholls, Jm" uniqKey="Nicholls J">JM Nicholls</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Cui, W" uniqKey="Cui W">W Cui</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Li, T" uniqKey="Li T">T Li</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, Yh" uniqKey="Wang Y">YH Wang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ng, Dl" uniqKey="Ng D">DL Ng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Channappanavar, R" uniqKey="Channappanavar R">R Channappanavar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Davidson, S" uniqKey="Davidson S">S Davidson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shaw, Ac" uniqKey="Shaw A">AC Shaw</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cheung, Cy" uniqKey="Cheung C">CY Cheung</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Law, Hk" uniqKey="Law H">HK Law</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yen, Yt" uniqKey="Yen Y">YT Yen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chien, Jy" uniqKey="Chien J">JY Chien</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, Ch" uniqKey="Wang C">CH Wang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wong, Ck" uniqKey="Wong C">CK Wong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhang, Y" uniqKey="Zhang Y">Y Zhang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cameron, Mj" uniqKey="Cameron M">MJ Cameron</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cameron, Mjrl" uniqKey="Cameron M">MJRL Cameron</name></author><author><name sortKey="Xu, L" uniqKey="Xu L">L Xu</name></author><author><name sortKey="Danesh, A" uniqKey="Danesh A">A Danesh</name></author><author><name sortKey="Bermejo Martin, Jf" uniqKey="Bermejo Martin J">JF Bermejo-Martin</name></author><author><name sortKey="Cameron, Cm" uniqKey="Cameron C">CM Cameron</name></author><author><name sortKey="Muller, Mp" uniqKey="Muller M">MP Muller</name></author><author><name sortKey="Gold, Wl" uniqKey="Gold W">WL Gold</name></author><author><name sortKey="Richardson, Se" uniqKey="Richardson S">SE Richardson</name></author><author><name sortKey="Poutanen, Sm" uniqKey="Poutanen S">SM Poutanen</name></author><author><name sortKey="Willey, Bm" uniqKey="Willey B">BM Willey</name></author><author><name sortKey="Devries, Me" uniqKey="Devries M">ME DeVries</name></author><author><name sortKey="Fang, Y" uniqKey="Fang Y">Y Fang</name></author><author><name sortKey="Seneviratne, C" uniqKey="Seneviratne C">C Seneviratne</name></author><author><name sortKey="Bosinger, Se" uniqKey="Bosinger S">SE Bosinger</name></author><author><name sortKey="Persad, D" uniqKey="Persad D">D Persad</name></author><author><name sortKey="Keshavjee, S" uniqKey="Keshavjee S">S Keshavjee</name></author><author><name sortKey="Louie, M" uniqKey="Louie M">M Louie</name></author><author><name sortKey="Loeb, Mb" uniqKey="Loeb M">MB Loeb</name></author><author><name sortKey="Brunton, J" uniqKey="Brunton J">J Brunton</name></author><author><name sortKey="Mcgeer, Aj" uniqKey="Mcgeer A">AJ McGeer</name></author><author><name sortKey="Kelvin, Dj" uniqKey="Kelvin D">DJ Kelvin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Huang, Kj" uniqKey="Huang K">KJ Huang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Theron, M" uniqKey="Theron M">M Theron</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lau, Sk" uniqKey="Lau S">SK Lau</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Tynell, J" uniqKey="Tynell J">J Tynell</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhou, J" uniqKey="Zhou J">J Zhou</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Scheuplein, Va" uniqKey="Scheuplein V">VA Scheuplein</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, Es" uniqKey="Kim E">ES Kim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Min, Ck" uniqKey="Min C">CK Min</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Roberts, A" uniqKey="Roberts A">A Roberts</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Day, Cw" uniqKey="Day C">CW Day</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nagata, N" uniqKey="Nagata N">N Nagata</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Roberts, A" uniqKey="Roberts A">A Roberts</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Frieman, Mb" uniqKey="Frieman M">MB Frieman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhao, J" uniqKey="Zhao J">J Zhao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Graham, Rl" uniqKey="Graham R">RL Graham</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rockx, B" uniqKey="Rockx B">B Rockx</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Smits, Sl" uniqKey="Smits S">SL Smits</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Totura, Al" uniqKey="Totura A">AL Totura</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jimenez Guardeno, Jm" uniqKey="Jimenez Guardeno J">JM Jimenez-Guardeno</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nieto Torres, Jl" uniqKey="Nieto Torres J">JL Nieto-Torres</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nieto Torres, Jl" uniqKey="Nieto Torres J">JL Nieto-Torres</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="De Wit, E" uniqKey="De Wit E">E de Wit</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Haagmans, Bl" uniqKey="Haagmans B">BL Haagmans</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Houser, Kv" uniqKey="Houser K">KV Houser</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Falzarano, D" uniqKey="Falzarano D">D Falzarano</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Johnson, Rf" uniqKey="Johnson R">RF Johnson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Barlan, A" uniqKey="Barlan A">A Barlan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhao, J" uniqKey="Zhao J">J Zhao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gretebeck, Lm" uniqKey="Gretebeck L">LM Gretebeck</name></author><author><name sortKey="Subbarao, K" uniqKey="Subbarao K">K Subbarao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Doremalen, N" uniqKey="Van Doremalen N">N van Doremalen</name></author><author><name sortKey="Munster, Vj" uniqKey="Munster V">VJ Munster</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pascal, Ke" uniqKey="Pascal K">KE Pascal</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Frieman, M" uniqKey="Frieman M">M Frieman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kindler, E" uniqKey="Kindler E">E Kindler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Narayanan, K" uniqKey="Narayanan K">K Narayanan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sun, L" uniqKey="Sun L">L Sun</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Thiel, V" uniqKey="Thiel V">V Thiel</name></author><author><name sortKey="Weber, F" uniqKey="Weber F">F Weber</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Totura, Al" uniqKey="Totura A">AL Totura</name></author><author><name sortKey="Baric, Rs" uniqKey="Baric R">RS Baric</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wathelet, Mg" uniqKey="Wathelet M">MG Wathelet</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Frieman, M" uniqKey="Frieman M">M Frieman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kopecky Bromberg, Sa" uniqKey="Kopecky Bromberg S">SA Kopecky-Bromberg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lu, Xl" uniqKey="Lu X">XL Lu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Siu, Kl" uniqKey="Siu K">KL Siu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lui, Py" uniqKey="Lui P">PY Lui</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yang, Y" uniqKey="Yang Y">Y Yang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chu, Cm" uniqKey="Chu C">CM Chu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ng, Ml" uniqKey="Ng M">ML Ng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Oh, Md" uniqKey="Oh M">MD Oh</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Herold, S" uniqKey="Herold S">S Herold</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hogner, K" uniqKey="Hogner K">K Hogner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rodrigue Gervais, Ig" uniqKey="Rodrigue Gervais I">IG Rodrigue-Gervais</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhao, J" uniqKey="Zhao J">J Zhao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, Kd" uniqKey="Kim K">KD Kim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Palm, Nw" uniqKey="Palm N">NW Palm</name></author><author><name sortKey="Medzhitov, R" uniqKey="Medzhitov R">R Medzhitov</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zornetzer, Ga" uniqKey="Zornetzer G">GA Zornetzer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Page, C" uniqKey="Page C">C Page</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gralinski, Le" uniqKey="Gralinski L">LE Gralinski</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Drosten, C" uniqKey="Drosten C">C Drosten</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lew, Tw" uniqKey="Lew T">TW Lew</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jiang, Y" uniqKey="Jiang Y">Y Jiang</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Stockman, Lj" uniqKey="Stockman L">LJ Stockman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Al Tawfiq, Ja" uniqKey="Al Tawfiq J">JA Al-Tawfiq</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Falzarano, D" uniqKey="Falzarano D">D Falzarano</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Omrani, As" uniqKey="Omrani A">AS Omrani</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Auyeung, Tw" uniqKey="Auyeung T">TW Auyeung</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ho, Jc" uniqKey="Ho J">JC Ho</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yam, Ly" uniqKey="Yam L">LY Yam</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Haagmans, Bl" uniqKey="Haagmans B">BL Haagmans</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Davidson, S" uniqKey="Davidson S">S Davidson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Blazek, K" uniqKey="Blazek K">K Blazek</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Imai, Y" uniqKey="Imai Y">Y Imai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shirey, Ka" uniqKey="Shirey K">KA Shirey</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Teijaro, Jr" uniqKey="Teijaro J">JR Teijaro</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Walsh, Kb" uniqKey="Walsh K">KB Walsh</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Leuschner, F" uniqKey="Leuschner F">F Leuschner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Leuschner, F" uniqKey="Leuschner F">F Leuschner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Darwish, I" uniqKey="Darwish I">I Darwish</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mcdermott, Je" uniqKey="Mcdermott J">JE McDermott</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">Semin Immunopathol</journal-id><journal-id journal-id-type="iso-abbrev">Semin Immunopathol</journal-id><journal-title-group><journal-title>Seminars in Immunopathology</journal-title></journal-title-group><issn pub-type="ppub">1863-2297</issn><issn pub-type="epub">1863-2300</issn><publisher><publisher-name>Springer Berlin Heidelberg</publisher-name><publisher-loc>Berlin/Heidelberg</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">28466096</article-id><article-id pub-id-type="pmc">7079893</article-id><article-id pub-id-type="publisher-id">629</article-id><article-id pub-id-type="doi">10.1007/s00281-017-0629-x</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review</subject></subj-group></article-categories><title-group><article-title>Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Channappanavar</surname><given-names>Rudragouda</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Perlman</surname><given-names>Stanley</given-names></name><address><phone>319-335-8549</phone><email>Stanley-perlman@uiowa.edu</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 8294</institution-id><institution-id institution-id-type="GRID">grid.214572.7</institution-id><institution>Department of Microbiology,</institution><institution>University of Iowa,</institution></institution-wrap>BSB 3-712, Iowa City, IA 52242 USA</aff></contrib-group><author-notes><fn fn-type="com"><p>This article is a contribution to the special issue on Cytokine Storm in Infectious Diseases - Guest Editor: John Teijaro</p></fn></author-notes><pub-date pub-type="epub"><day>2</day><month>5</month><year>2017</year></pub-date><pub-date pub-type="ppub"><year>2017</year></pub-date><volume>39</volume><issue>5</issue><fpage>529</fpage><lpage>539</lpage><history><date date-type="received"><day>9</day><month>11</month><year>2016</year></date><date date-type="accepted"><day>10</day><month>4</month><year>2017</year></date></history><permissions><copyright-statement>© Springer-Verlag Berlin Heidelberg 2017</copyright-statement><license><license-p>This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.</license-p></license></permissions><abstract id="Abs1"><p id="Par1">Human coronaviruses (hCoVs) can be divided into low pathogenic and highly pathogenic coronaviruses. The low pathogenic CoVs infect the upper respiratory tract and cause mild, cold-like respiratory illness. In contrast, highly pathogenic hCoVs such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) predominantly infect lower airways and cause fatal pneumonia. Severe pneumonia caused by pathogenic hCoVs is often associated with rapid virus replication, massive inflammatory cell infiltration and elevated pro-inflammatory cytokine/chemokine responses resulting in acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Recent studies in experimentally infected animal strongly suggest a crucial role for virus-induced immunopathological events in causing fatal pneumonia after hCoV infections. Here we review the current understanding of how a dysregulated immune response may cause lung immunopathology leading to deleterious clinical manifestations after pathogenic hCoV infections.</p></abstract><kwd-group xml:lang="en"><title>Keywords</title><kwd>SARS-CoV</kwd><kwd>MERS-CoV</kwd><kwd>Cytokine storm</kwd><kwd>Immunopathology</kwd><kwd>Interferon</kwd><kwd>Monocyte-macrophage</kwd></kwd-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© Springer-Verlag GmbH Germany 2017</meta-value></custom-meta></custom-meta-group></article-meta></front><body><sec id="Sec1"><title>Introduction</title><p id="Par2">Coronaviruses belong to the virus family Coronaviridae and are enveloped, positive-sense RNA viruses. The coronavirus genome is approximately 31 Kb, making these viruses the largest known RNA viruses [<xref ref-type="bibr" rid="CR1">1</xref>, <xref ref-type="bibr" rid="CR2">2</xref>]. Coronaviruses infect a variety of host species, including humans and several other vertebrates. These viruses predominantly cause respiratory and intestinal tract infections and induce a wide range of clinical manifestations [<xref ref-type="bibr" rid="CR3">3</xref>, <xref ref-type="bibr" rid="CR4">4</xref>]. Coronaviruses infecting the respiratory tract have long been recognized as significant pathogens in domestic and companion animals and as the cause of mild and severe respiratory illness in humans [<xref ref-type="bibr" rid="CR4">4</xref>, <xref ref-type="bibr" rid="CR5">5</xref>]. In general, coronaviruses infecting humans can be classified into low pathogenic hCoVs, which include HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU and highly pathogenic CoVs such as severe acute respiratory syndrome CoV (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) [<xref ref-type="bibr" rid="CR6">6</xref>, <xref ref-type="bibr" rid="CR7">7</xref>]. Low pathogenic hCoV infect upper airways and cause seasonal mild to moderate cold-like respiratory illnesses in healthy individuals. In contrast, the highly pathogenic hCoVs (pathogenic hCoV or hCoV hereafter) infect the lower respiratory tract and cause severe pneumonia, which sometimes leads to fatal acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), resulting in high morbidity and mortality [<xref ref-type="bibr" rid="CR8">8</xref>–<xref ref-type="bibr" rid="CR12">12</xref>].</p><p id="Par3">Highly pathogenic hCoVs pose a substantial threat to public health. During the 2002–2003 epidemic, SARS-CoV infected approximately 8400 individuals with a 9.6% overall mortality rate [<xref ref-type="bibr" rid="CR13">13</xref>, <xref ref-type="bibr" rid="CR14">14</xref>]. More recently, MERS-CoV crossed species to infect 1936 individuals resulting in 690 deaths (∼36% mortality rate) as of April 5, 2017 [<xref ref-type="bibr" rid="CR15">15</xref>, <xref ref-type="bibr" rid="CR16">16</xref>]. Recent identification of SARS-like coronaviruses in bats and MERS-CoV in domesticated camels makes it likely that these viruses will continue to cross species barriers and cause additional outbreaks in human populations [<xref ref-type="bibr" rid="CR17">17</xref>–<xref ref-type="bibr" rid="CR20">20</xref>]. These highly pathogenic hCoVs cause a wide spectrum of clinical manifestations in humans, with a large fraction of patients developing short period of moderate clinical illness and a small but a substantial number of patients experiencing severe disease characterized by ALI and ARDS [<xref ref-type="bibr" rid="CR21">21</xref>–<xref ref-type="bibr" rid="CR23">23</xref>, <xref ref-type="bibr" rid="CR10">10</xref>]. Thus, there are basically two groups of patients, those developing milder disease, which resolved and those with severe disease, which was commonly fatal. The disease severity in pathogenic hCoV infections was also influenced by several factors such as initial viral titers in the airways and age and comorbid conditions of the infected individual. While younger individuals below 18 years experience mild-moderate clinical illness, elderly individuals exhibit worse outcomes after infection with SARS-CoV or MERS-CoV [<xref ref-type="bibr" rid="CR22">22</xref>, <xref ref-type="bibr" rid="CR10">10</xref>, <xref ref-type="bibr" rid="CR24">24</xref>]. Additionally, individuals with comorbid conditions such as diabetes, obesity, heart failure, and renal failure among others experience severe disease, particularly after MERS-CoV infection [<xref ref-type="bibr" rid="CR25">25</xref>, <xref ref-type="bibr" rid="CR26">26</xref>].</p><p id="Par4">Despite several years of research, specific factors causing the unusually high morbidity and mortality following pathogenic hCoVs are incompletely understood. Virus-induced direct cytopathic effects and viral evasion of host immune responses are believed to play major roles in disease severity. However, studies from humans who died of SARS and more recent studies in animal models suggested that a dysregulated immune response occurred, resulting in an exuberant inflammation and lethal disease. In this review, we discuss recent advances in our understanding of hCoV pathogenesis, with a special emphasis on cytokine storm and immunopathology as causes for deleterious consequences during hCoV infections.</p></sec><sec id="Sec2"><title>Clinical features of highly pathogenic CoV infection in humans</title><p id="Par5">SARS-CoV infection in humans resulted in an acute respiratory illness that varied from mild febrile illness to ALI and in some cases ARDS and death [<xref ref-type="bibr" rid="CR27">27</xref>, <xref ref-type="bibr" rid="CR10">10</xref>]. The clinical course of SARS presents in three distinct phases. The initial phase was characterized by robust virus replication accompanied by fever, cough, and other symptoms, all of which subsided in a few days. The second clinical phase was associated with high fever, hypoxemia, and progression to pneumonia-like symptoms, despite a progressive decline in virus titers towards the end of this phase [<xref ref-type="bibr" rid="CR28">28</xref>]. During the third phase, ∼20% of patients progressed to ARDS, which often resulted in death [<xref ref-type="bibr" rid="CR29">29</xref>, <xref ref-type="bibr" rid="CR30">30</xref>]. Because of a progressive decline in virus titers, the third phase is thought to have resulted from exuberant host inflammatory responses.</p><p id="Par6">The most common clinical manifestations of MERS include flu-like symptoms such as fever, sore throat, non-productive cough, myalgia, shortness of breath, and dyspnea, which rapidly progress to pneumonia [<xref ref-type="bibr" rid="CR25">25</xref>, <xref ref-type="bibr" rid="CR21">21</xref>]. Other atypical presentations include mild respiratory illness without fever, chills, wheezing, and palpitations. MERS-CoV in humans also causes gastrointestinal symptoms such as abdominal pain, vomiting, and diarrhea. The majority of MERS patients with dyspnea progress to develop severe pneumonia and require admission to an intensive care unit (ICU). Although most healthy individuals present with mild-moderate respiratory illness, immunocompromised and individuals with comorbid conditions experience severe respiratory illness, which often progressed to ARDS [<xref ref-type="bibr" rid="CR21">21</xref>]. Overall, MERS-CoV caused severe disease in primary index cases, immunocompromised individuals and in patients with comorbid conditions, but secondary cases of household contacts or healthcare workers were mostly asymptomatic or showed mild respiratory illness.</p></sec><sec id="Sec3"><title>Lung pathology of hCoV infections</title><sec id="Sec4"><title>Gross and microscopic pathology of SARS</title><p id="Par7">Typically, analyses of lungs from patients who succumbed to SARS showed lung consolidation and edema with pleural effusions, focal hemorrhages, and mucopurulent material in the tracheobronchial tree. Diffuse alveolar damage (DAD) was a prominent histological feature in SARS lungs [<xref ref-type="bibr" rid="CR31">31</xref>, <xref ref-type="bibr" rid="CR32">32</xref>]. Other changes included hyaline membrane formation, alveolar hemorrhage, and fibrin exudation in alveolar spaces with septal and alveolar fibrosis observed during later stages [<xref ref-type="bibr" rid="CR32">32</xref>, <xref ref-type="bibr" rid="CR33">33</xref>]. Staining for viral antigen revealed infection of airway and alveolar epithelial cells, vascular endothelial cells, and macrophages [<xref ref-type="bibr" rid="CR31">31</xref>, <xref ref-type="bibr" rid="CR32">32</xref>]. Furthermore, SARS-CoV viral particles and viral genome were also detected in monocytes and lymphocytes [<xref ref-type="bibr" rid="CR31">31</xref>].</p><p id="Par8">In addition to these changes, histological examination of lungs from patients who died of SARS revealed extensive cellular infiltrates in the interstitium and alveoli. These cellular infiltrates included neutrophils and macrophages with macrophages being the predominant cell type [<xref ref-type="bibr" rid="CR31">31</xref>, <xref ref-type="bibr" rid="CR32">32</xref>]. These results correlated with increased numbers of neutrophils and monocytes and lower CD4 and CD8 T cell counts in the peripheral blood samples of patients with fatal SARS [<xref ref-type="bibr" rid="CR34">34</xref>–<xref ref-type="bibr" rid="CR36">36</xref>].</p></sec><sec id="Sec5"><title>Gross and microscopic pathology of MERS</title><p id="Par9">Despite numerous laboratory-confirmed cases and deaths due to MERS-CoV infection in several countries, only one autopsy report of MERS in humans is available. Analysis of lung tissue from this patient showed pleural, pericardial, and abdominal effusions associated with generalized congestion, edema, and consolidation of lungs [<xref ref-type="bibr" rid="CR37">37</xref>]. Similar to SARS-CoV infection, DAD was a prominent feature in the lungs. Additionally, epithelial cell necrosis, sloughing of bronchiolar epithelium, alveolar edema, and thickening of alveolar septa were also noted. Immunohistochemical examination showed that MERS-CoV predominantly infected airways and alveolar epithelial cells, and endothelial cells and macrophages. The severity of lung lesions correlated with extensive infiltration of neutrophils and macrophages in the lungs and higher numbers of these cells in the peripheral blood of MERS patients [<xref ref-type="bibr" rid="CR37">37</xref>].</p></sec></sec><sec id="Sec6"><title>Cytokine and chemokine responses during pathogenic hCoV infections</title><p id="Par10">Cytokines and chemokines have long been thought to play an important role in immunity and immunopathology during virus infections. A rapid and well-coordinated innate immune response is the first line of defense against viral infections, but dysregulated and excessive immune responses may cause immunopathology [<xref ref-type="bibr" rid="CR38">38</xref>–<xref ref-type="bibr" rid="CR40">40</xref>]. Although there is no direct evidence for the involvement of pro-inflammatory cytokines and chemokines in lung pathology during SARS and MERS, correlative evidence from patients with severe disease suggests a role for hyper-inflammatory responses in hCoV pathogenesis.</p><sec id="Sec7"><title>Cytokine and chemokine responses to SARS-CoV infection</title><p id="Par11">While SARS-CoV productively infects airway and alveolar epithelial cells, infection of hematopoietic cells such as dendritic cells (DCs), monocyte-macrophages, and other PBMC-derived cells is abortive. SARS-CoV infection of DCs induces low-level expression of antiviral cytokines IFN-αβ, moderate up-regulation of pro-inflammatory cytokines TNF and IL-6, and a significant up-regulation of inflammatory chemokines CCL3, CCL5, CCL2, and CXCL10 [<xref ref-type="bibr" rid="CR41">41</xref>, <xref ref-type="bibr" rid="CR42">42</xref>]. Similarly, SARS-CoV-infected macrophages show delayed but elevated levels of IFN and other pro-inflammatory cytokines [<xref ref-type="bibr" rid="CR42">42</xref>]. Additionally, SARS-CoV-infected airway epithelial cells (AECs) also produce large amounts of CCL3, CCL5, CCL2, and CXCL10 [<xref ref-type="bibr" rid="CR43">43</xref>]. The delayed but excessive production of these cytokines and chemokines is thought to induce a dysregulated innate immune response to SARS-CoV infection.</p><p id="Par12">High serum levels of pro-inflammatory cytokines (IFN-γ, IL-1, IL-6, IL-12, and TGFβ) and chemokines (CCL2, CXCL10, CXCL9, and IL-8) were found in SARS patients with severe disease compared to individuals with uncomplicated SARS [<xref ref-type="bibr" rid="CR44">44</xref>–<xref ref-type="bibr" rid="CR47">47</xref>]. Conversely, SARS patients with severe disease had very low levels of the anti-inflammatory cytokine, IL-10 [<xref ref-type="bibr" rid="CR44">44</xref>]. In addition to pro-inflammatory cytokines and chemokines, individuals with lethal SARS showed elevated levels of IFN (IFN-α and IFN-γ) and IFN-stimulated genes (ISGs) (CXCL10 and CCL-2) compared to healthy controls or individuals with mild-moderate disease [<xref ref-type="bibr" rid="CR48">48</xref>–<xref ref-type="bibr" rid="CR51">51</xref>]. These results were the first to suggest a possible role for IFNs and ISGs in the immunopathogenesis of SARS in humans. Thus, it appears from these studies that dysregulated and/or exaggerated cytokine and chemokine responses by SARS-CoV-infected AECs, DCs, and macrophages could play an important role in SARS pathogenesis.</p></sec><sec id="Sec8"><title>Cytokine and chemokine responses to MERS-CoV infection</title><p id="Par13">Similar to SARS, MERS-CoV infection of human airway epithelial cells induces significant but delayed IFN and pro-inflammatory cytokine (IL-1β, IL-6, and IL-8) responses [<xref ref-type="bibr" rid="CR52">52</xref>]. While MERS-CoV replicates both in naïve and activated human monocyte-macrophages and DCs, only activated T cells support MERS-CoV replication [<xref ref-type="bibr" rid="CR53">53</xref>–<xref ref-type="bibr" rid="CR55">55</xref>]. This is in contrast to SARS-CoV, which abortively infected monocyte-macrophages, DCs, and T cells. MERS-CoV infection of THP-1 cells, a monocyte cell line, and human peripheral blood monocyte-derived macrophages and dendritic cells induced delayed but elevated levels of pro-inflammatory cytokines and chemokines such as CCL-2, CCL-3, CCL-5, IL-2, and IL-8 [<xref ref-type="bibr" rid="CR54">54</xref>, <xref ref-type="bibr" rid="CR55">55</xref>]. However, induction of IFN-α/β by monocyte-macrophages and DCs was not substantial except for plasmacytoid dendritic cells, which produced copious amounts of IFNs upon MERS-CoV infection [<xref ref-type="bibr" rid="CR56">56</xref>]. Recent studies showed elevated levels of serum pro-inflammatory cytokines (IL-6 and IFN-α) and chemokines (IL-8, CXCL-10, and CCL5) in individuals with severe MERS compared to those with mild to moderate disease [<xref ref-type="bibr" rid="CR57">57</xref>, <xref ref-type="bibr" rid="CR58">58</xref>]. High serum cytokine and chemokine levels in MERS patients correlated with increased neutrophil and monocyte numbers in lungs and in the peripheral blood, suggesting a possible role for these cells in lung pathology [<xref ref-type="bibr" rid="CR57">57</xref>, <xref ref-type="bibr" rid="CR58">58</xref>, <xref ref-type="bibr" rid="CR37">37</xref>].</p></sec></sec><sec id="Sec9"><title>Cytokines/chemokines and immunopathology in animal models</title><sec id="Sec10"><title>Dysregulated inflammatory response in animal models of SARS-CoV infection</title><p id="Par14">Several inbred mouse strains have been evaluated to study SARS-CoV pathogenesis. Mice infected with the human strain of SARS-CoV (SARS-CoV-Urbani) were permissive to virus replication but developed only mild lung pathology and clinical illness [<xref ref-type="bibr" rid="CR59">59</xref>]. Subsequently, isolation of mouse-adapted strains of SARS-CoV (e.g., SARS-CoV-MA15) allowed studies of lethal SARS [<xref ref-type="bibr" rid="CR60">60</xref>–<xref ref-type="bibr" rid="CR62">62</xref>]. MA15 infects airway and alveolar epithelial cells and epithelial cells of other organs [<xref ref-type="bibr" rid="CR62">62</xref>]. Young mice of many strains (e.g., C57BL/6, 129) support MA15 replication in the lungs but are resistant to developing significant clinical disease [<xref ref-type="bibr" rid="CR63">63</xref>, <xref ref-type="bibr" rid="CR64">64</xref>]. In contrast, young BALB/c mice infected with MA15 develop lethal disease characterized by diffuse alveolar damage, enhanced monocyte/macrophage and neutrophil accumulation, pulmonary edema, and hyaline membrane formation [<xref ref-type="bibr" rid="CR62">62</xref>]. Furthermore, aged mice of all strains develop lethal clinical disease and succumb to infection [<xref ref-type="bibr" rid="CR65">65</xref>, <xref ref-type="bibr" rid="CR66">66</xref>, <xref ref-type="bibr" rid="CR64">64</xref>]. In addition to mouse models, SARS-CoV infection of aged rhesus macaques resulted in significantly more pathology than young adult animals [<xref ref-type="bibr" rid="CR67">67</xref>]. These animal models replicated several key features of SARS-CoV infection in humans and were thus useful for investigating SARS pathogenesis.</p><p id="Par15">Studies in animal models have been particularly useful in elucidating the role of cytokines and chemokines in mediating lung immunopathology following hCoV infections. Infection of non-human primates (NHPs) with SARS-CoV induced a dysregulated immune response resulting in increased disease severity in aged but not young NHPs, despite similar viral titers in the airways [<xref ref-type="bibr" rid="CR67">67</xref>]. Since enhanced expression of genes regulating inflammation but not virus titers correlated with disease severity, an exaggerated immune response is thought to induce lethal disease in aged NHPs [<xref ref-type="bibr" rid="CR67">67</xref>]. Similarly, in SARS-CoV-infected BALB/c mice, disease severity in aged mice correlated with early and disproportionately strong up-regulation of ARDS-associated inflammatory gene signatures [<xref ref-type="bibr" rid="CR66">66</xref>]. In a recent study, we identified a pathogenic role for IFN-I in mice infected with MA15. Our results showed that rapid SARS-CoV replication in BALB/c mice induced a delayed IFN-α/β response accompanied by an excessive influx of pathogenic inflammatory monocyte-macrophages (IMMs) [<xref ref-type="bibr" rid="CR38">38</xref>]. The accumulating IMMs themselves produced additional levels of monocyte chemo-attractants such as CCL2, CCL7, and CCL12 (through IFN-α/β receptor stimulation), resulting in further accumulation of pathogenic IMMs, which in turn enhanced disease severity. These infiltrating IMMs produced elevated levels of pro-inflammatory cytokines such as TNF, IL-6, IL1-β, and iNOS. Blocking IFN signaling, depleting IMMs, or neutralizing a single inflammatory cytokine, TNF, protected mice from lethal SARS-CoV infection. Additionally, IFN-α/β or IMM-derived pro-inflammatory cytokines sensitized T cells to undergo apoptosis, further impeding virus clearance [<xref ref-type="bibr" rid="CR38">38</xref>]. In another study of SARS-CoV infection, loss of TIR-domain-containing adapter-inducing interferon-β (TRIF), an adapter molecule for TLR3 and TLR4 signaling, resulted in a distinct inflammatory signature characterized by neutrophil and other inflammatory cell infiltration [<xref ref-type="bibr" rid="CR68">68</xref>]. A dysregulated immune response to SARS-CoV in TRIF-deficient mice was associated with aberrant antiviral IFN (IFN-α and IFNβ), pro-inflammatory cytokine and chemokine (IL-6, TNF, IFN-γ, and CCL5), and interferon-stimulated gene (RSAD2, IFIT1, and CXCL10) responses. Notably, virus titers were significantly higher in TLR3<sup>−/−</sup> and TRIF<sup>−/−</sup> mice compared to their WT controls [<xref ref-type="bibr" rid="CR68">68</xref>]. Although the viral factors regulating the pro-inflammatory response of neutrophils and monocyte-macrophages remain to be identified, the E protein of SARS-CoV has been shown to enhance pro-inflammatory cytokine and chemokine and inflammasome activity via its ion channel activity [<xref ref-type="bibr" rid="CR69">69</xref>–<xref ref-type="bibr" rid="CR71">71</xref>]. These results support the notion that higher virus titers and dysregulated cytokine/chemokine responses cause a “cytokine storm” with lung immunopathological changes following SARS-CoV infection.</p></sec><sec id="Sec11"><title>Animal models of MERS-CoV infection and lethal disease</title><p id="Par16">Animal models employed to study MERS include rhesus macaques, rabbits, marmosets, and mice among others. MERS-CoV challenged rhesus macaques developed mild to moderate disease [<xref ref-type="bibr" rid="CR72">72</xref>]. Similarly, MERS-CoV-infected rabbits displayed mild clinical disease with mild-moderate perivascular, peribronchiolar infiltration, and to a lesser extent lung interstitial inflammation [<xref ref-type="bibr" rid="CR73">73</xref>, <xref ref-type="bibr" rid="CR74">74</xref>]. In contrast, marmosets displayed moderate-severe respiratory disease characterized by broncho-interstitial pneumonia, alveolar edema, and fibrin deposition [<xref ref-type="bibr" rid="CR75">75</xref>]. Marmosets with severe disease showed increased neutrophil and macrophage infiltration in alveoli and interstitial septa, although whether marmosets develop severe disease remains controversial [<xref ref-type="bibr" rid="CR75">75</xref>, <xref ref-type="bibr" rid="CR76">76</xref>]. Although gross and histological lesions and inflammatory cell infiltration in MERS-CoV infected marmosets resemble human disease, there are no data available describing cytokine and chemokine responses in these animals.</p><p id="Par17">Small laboratory animals, particularly rodents, do not support MERS-CoV replication due to inability of MERS-CoV-spike protein to bind to human DPP4 (hDPP4) orthologs in these animals [<xref ref-type="bibr" rid="CR77">77</xref>]. The first mouse model to study MERS was generated by intranasal transduction of adenovirus encoding hDPP4. These mice developed mild to moderate pneumonia, especially in immunodeficient mice [<xref ref-type="bibr" rid="CR78">78</xref>]. Several hDPP4 transgenic mouse models developed thereafter exhibited variable organ tropism and disease severity, depending on the promoter driving the hDPP4 expression [<xref ref-type="bibr" rid="CR79">79</xref>, <xref ref-type="bibr" rid="CR80">80</xref>]. More recently, hDPP4 knock-in mice in which hDPP4 is expressed under the mouse hDPP4 promoter have also been described. These mice also developed moderate clinical disease after infection with human isolates of MERS-CoV [<xref ref-type="bibr" rid="CR81">81</xref>]. We and others recently developed a similar mouse model and showed that serial passage of human isolate of MERS-CoV resulted in mouse adaptation. Mice infected with this adapted virus caused lethal respiratory illness and will be useful for studies of pathogenesis [<xref ref-type="bibr" rid="CR82">82</xref>, <xref ref-type="bibr" rid="CR83">83</xref>].</p><p id="Par18">Overall, delayed and aberrant antiviral and pro-inflammatory cytokine production in MERS-CoV-infected human macrophages and dendritic cells and high serum pro-inflammatory cytokine levels in patients with severe disease compared to mild-moderate clinical disease suggesting that possible dysregulated and enhanced cytokine responses promote lung pathology following MERS-CoV infection.</p></sec></sec><sec id="Sec12"><title>CoV antagonism of IFN responses and disease severity</title><p id="Par19">To counter innate antiviral cytokine responses, SARS-CoV and MERS-CoV encode several structural and non-structural proteins (nsps) that antagonize antiviral immune response. SARS-CoV encoded nsp1, nsp3-macrodomain, nsp3-deubiquitinase (DUB), and ORF3b, ORF6, and ORF9b subvert antiviral response by antagonizing IFN and ISG responses [<xref ref-type="bibr" rid="CR84">84</xref>–<xref ref-type="bibr" rid="CR89">89</xref>]. While nsp3 impairs IFN responses by unknown mechanism, nsp1 inhibits IFN responses by blocking STAT1 phosphorylation [<xref ref-type="bibr" rid="CR90">90</xref>, <xref ref-type="bibr" rid="CR91">91</xref>]. Additionally, structural proteins such as the membrane (M) and nucleocapsid (N) proteins dampen IFN signaling by inhibiting TBK1/IKKe and by unknown mechanisms, respectively [<xref ref-type="bibr" rid="CR92">92</xref>–<xref ref-type="bibr" rid="CR95">95</xref>]. Similarly, MERS-CoV structural proteins M and N and accessory proteins orf3, orf4a, and orf4b antagonize IFN responses [<xref ref-type="bibr" rid="CR85">85</xref>, <xref ref-type="bibr" rid="CR96">96</xref>, <xref ref-type="bibr" rid="CR97">97</xref>]. It should be noted that most if not all of these putative antiviral mechanisms were demonstrated in transient expression assays and whether they are actually important in the context of infectious virus remains to be determined. Structural and non-structural protein antagonism of IFN responses further amplifies inflammatory responses by promoting unrestrained virus replication resulting in increased viral PAMPs that further dampen IFN signaling and stimulate PRRs to induce an aberrant inflammatory response. Lack of IFN signaling also leads to an excessive accumulation of Ly6C low monocytes and neutrophils.</p></sec><sec id="Sec13"><title>Causes of exuberant inflammatory response</title><p id="Par20">Despite several years of research studying SARS and MERS pathogenesis, specific host factors that drive lung pathology following hCoV infections are relatively unknown. However, a careful review of the literature related to SARS-CoV and MERS-CoV pathogenesis in humans and animal models highlights several key factors that may play a crucial role in the initiation and progression of an exacerbated inflammatory responses.<list list-type="order"><list-item><p id="Par21"><italic>Rapid virus replication</italic>: A notable feature of pathogenic human coronaviruses such as SARS-CoV and MERS-CoV is that both viruses replicate to high titers very early after infection both in vitro and in vivo [<xref ref-type="bibr" rid="CR38">38</xref>, <xref ref-type="bibr" rid="CR98">98</xref>–<xref ref-type="bibr" rid="CR100">100</xref>, <xref ref-type="bibr" rid="CR28">28</xref>]. This high replication could lead to enhanced cytopathic effects and production of higher levels of pro-inflammatory cytokines and chemokines by infected epithelial cells [<xref ref-type="bibr" rid="CR99">99</xref>, <xref ref-type="bibr" rid="CR68">68</xref>, <xref ref-type="bibr" rid="CR12">12</xref>]. These cytokines and chemokines in turn orchestrate massive infiltration of inflammatory cells into the lungs [<xref ref-type="bibr" rid="CR38">38</xref>]. Studies from hCoV infections in humans and experimental animals demonstrated a strong correlation between high SARS-CoV and MERS-CoV titers and disease severity.</p></list-item><list-item><p id="Par22"><italic>hCoV infection of airway and/or alveolar epithelial cells</italic>: Studies from animal models, especially mouse models, provide correlative evidence for differential disease outcome if the viruses predominantly infect airway epithelial cells versus both airway and alveolar epithelial (type I and type II pneumocytes) cells. In B6 and 129 strains, both of which are permissive to virus replication but resistant to developing clinical disease, viral antigen is predominantly located in airway epithelial cells early after infection. In contrast, in highly susceptible BALB/c mice, virus antigen is detected in the lung airways and in alveolar type I and II pneumocytes (Fig. <xref rid="Fig1" ref-type="fig">1</xref>). These results suggest a critical role for hCoV-infected type I and II pneumocytes in mediating lung pathology and host susceptibility.</p></list-item><list-item><p id="Par23"><italic>Delayed IFN responses</italic>: As mentioned in previous sections, both SARS-CoV and MERS-CoV encode multiple structural and non-structural proteins that antagonize IFN responses. hCoV reach high titers very early after infection and harbor multiple proteins that inhibit the IFN response, suggesting that an early antagonism of the IFN response might delay or evade the innate immune response. The delayed IFN signaling further orchestrates IMM responses and sensitizes T cells to apoptosis resulting in dysregulated inflammatory response [<xref ref-type="bibr" rid="CR38">38</xref>].</p></list-item><list-item><p id="Par24"><italic>Monocyte-macrophages and neutrophil accumulation</italic>: Both human and animal studies demonstrate accumulation of inflammatory monocyte-macrophages and neutrophils in the lungs following hCoV infection. These cells are the predominant source of cytokines and chemokines associated with hCoV lethal disease observed both in humans and animal models [<xref ref-type="bibr" rid="CR38">38</xref>, <xref ref-type="bibr" rid="CR32">32</xref>].</p></list-item></list><fig id="Fig1"><label>Fig. 1</label><caption><p>Staining for SARS-CoV-N antigen in lungs of C57BL/6 and BALB/c mice at 16 and 48 h post-infection</p></caption><graphic xlink:href="281_2017_629_Fig1_HTML" id="MO1"></graphic></fig></p></sec><sec id="Sec14"><title>Consequences of cytokine storm and immunopathology</title><p id="Par25"><list list-type="order"><list-item><p id="Par26"><italic>Epithelial and endothelial cell apoptosis and vascular leakage</italic>: One of the earliest consequences of rapid virus replication and exuberant pro-inflammatory cytokine/chemokine responses is lung epithelial and endothelial cell apoptosis. IFN-αβ and IFN-γ induce inflammatory cell infiltration and cause airway and alveolar epithelial cell apoptosis via Fas-FasL- or TRAIL-DR5-dependent mechanisms [<xref ref-type="bibr" rid="CR101">101</xref>–<xref ref-type="bibr" rid="CR103">103</xref>]. Additionally, TNF released by IMMs also promotes the apoptosis of both lung epithelial cells and endothelial cells (unpublished observation). Apoptosis of epithelial and endothelial cells compromises lung microvascular and alveolar epithelial cell barrier resulting in vascular leakage and alveolar edema ultimately resulting in hypoxia.</p></list-item><list-item><p id="Par27"><italic>Suboptimal T cell response</italic>: CoV-specific T cells are crucial for virus clearance and limit further damage to host [<xref ref-type="bibr" rid="CR64">64</xref>, <xref ref-type="bibr" rid="CR104">104</xref>]. Additionally, T cell responses also dampen overactive innate immune responses [<xref ref-type="bibr" rid="CR105">105</xref>, <xref ref-type="bibr" rid="CR106">106</xref>]. Exuberant inflammatory responses caused by pathogenic hCoV diminish the T cell response, in the case of SARS-CoV infection via TNF-mediated T cell apoptosis, thus resulting in uncontrolled inflammatory response.</p></list-item><list-item><p id="Par28"><italic>Accumulation of alternatively activated macrophages and altered tissue homeostasis</italic>: In some SARS patients with extended duration of disease, DAD was accompanied by fibrosis of interstitial and alveolar spaces and hyperplasia of pneumocytes. Similar histological features were noticed in lungs of SARS-CoV-challenged <italic>STAT</italic><sup><italic>−/−</italic></sup> mice on B6 and 129 backgrounds. Lungs from these mice revealed an enhanced perivascular infiltration of alternatively activated macrophages, neutrophils, and fibroblasts accompanied by extensive fibrin deposition and alveolar collapse, features observed during end stage ALI and ARDS in humans [<xref ref-type="bibr" rid="CR63">63</xref>, <xref ref-type="bibr" rid="CR107">107</xref>]. Further studies revealed that abrogation of <italic>STAT1</italic> signaling, specifically in myeloid cells, resulted in alternative activation of macrophages [<xref ref-type="bibr" rid="CR108">108</xref>]. In addition, a delicate balance between host coagulation and fibrinolysis processes regulates tissue remodeling and ALI [<xref ref-type="bibr" rid="CR109">109</xref>].</p></list-item><list-item><p id="Par29"><italic>ARDS</italic>: Inflammatory mediators play a key role in the pathogenesis of ARDS, a primary cause of death in patients infected with SARS-CoV or MERS-CoV [<xref ref-type="bibr" rid="CR110">110</xref>, <xref ref-type="bibr" rid="CR111">111</xref>]. Several pro-inflammatory cytokines, including IL-6, IL-8, IL-1β, and GM-CSF, reactive oxygen species, and chemokines such as CCL2, CCL-5, IP-10, and CCL3 contribute to ARDS [<xref ref-type="bibr" rid="CR48">48</xref>, <xref ref-type="bibr" rid="CR112">112</xref>, <xref ref-type="bibr" rid="CR113">113</xref>]. Additionally, uncontrolled epithelial cell proliferation and impaired tissue remodeling during later stages induce ARDS leading to pulmonary fibrosis and death.</p></list-item></list></p><p id="Par30">A summary of causes and consequences of cytokine storm and immunopathology to hCoV pathogenesis is demonstrated in Fig. <xref rid="Fig2" ref-type="fig">2</xref>.<fig id="Fig2"><label>Fig. 2</label><caption><p>Schematic representation of protective versus pathogenic inflammatory responses to pathogenic hCoV infections</p></caption><graphic xlink:href="281_2017_629_Fig2_HTML" id="MO2"></graphic></fig></p></sec><sec id="Sec15"><title>Therapeutic approaches</title><p id="Par31">High virus titers and subsequent exuberant inflammatory cytokine and chemokine responses correlate with high morbidity and mortality observed during pathogenic hCoV infections. A systematic review of therapeutic effects of several commonly used antiviral and immunomodulatory agents used during SARS outbreak showed inconclusive results [<xref ref-type="bibr" rid="CR114">114</xref>]. Similarly, therapeutic interventions aimed towards reducing viral load were somewhat beneficial when administered early but not during later stages of MERS-CoV infection [<xref ref-type="bibr" rid="CR115">115</xref>–<xref ref-type="bibr" rid="CR117">117</xref>]. These results suggest that besides controlling viral load, novel strategies directed at attenuating inflammatory responses will likely improve clinical outcomes. Here, we describe agents that have the potential to mitigate hCoV-induced inflammation.</p><sec id="Sec16"><title>Commonly used therapeutics</title><sec id="FPar3"><title>Corticosteroid therapy</title><p id="Par32">Corticosteroids are a class of steroidal hormones that exert anti-inflammatory functions and are generally used to suppress inflammatory conditions. During the 2003 SARS epidemic, corticosteroids were the mainstay of immunomodulatory therapy. The timely administration of corticosteroids often leads to early improvement in terms of reduced fever, resolution of radiographic lung infiltrates, and better oxygenation [<xref ref-type="bibr" rid="CR118">118</xref>–<xref ref-type="bibr" rid="CR120">120</xref>]. However, while some studies showed no beneficial effect, other demonstrated adverse outcomes following corticosteroid therapy during SARS-CoV infection in humans. Early treatment of corticosteroids in SARS patients enhanced plasma viral load in non-ICU patients, thus leading to exacerbated disease [<xref ref-type="bibr" rid="CR118">118</xref>]. Overall, these results show that the timing, dosage, and duration of corticosteroid therapy are critical if this intervention is to be beneficial in hCoV infections. In general, corticosteroid therapy is not recommended for treatment of hCoV respiratory infections.</p></sec><sec id="FPar4"><title>Interferons</title><p id="Par33">Pegylated and non-pegylated interferons have been under investigation for therapeutic purposes in hCoV-infected individuals. However, therapeutic use of these agents produced mixed results both in humans and animal models of hCoV infections. Early administration of IFN was marginally beneficial in reducing viral load and resulted in moderate improvement in clinical manifestations. In contrast, delayed administration of IFN did not have any advantage compared to placebo controls. Similarly, early administration of combination of IFN and ribavirin modestly ameliorated disease severity but did not affect mortality [<xref ref-type="bibr" rid="CR115">115</xref>, <xref ref-type="bibr" rid="CR121">121</xref>, <xref ref-type="bibr" rid="CR117">117</xref>, <xref ref-type="bibr" rid="CR122">122</xref>].</p></sec></sec><sec id="Sec17"><title>Other possible therapeutics</title><sec id="FPar5"><title>IFN-αβ inhibitors and IFN-λ</title><p id="Par34">IFN-αβ restrict virus replication through induction of ISGs. However, IFN-αβ can also exacerbate disease by enhancing recruitment and function of IMMs and other innate immune cells. While an early interferon response was protective in SARS-CoV-infected mice, delayed IFN-αβ signaling dysregulated the anti-SARS-CoV immune response suggesting that timing of IFN therapy is critical in determining the disease outcome. Based on these results, the administration of IFN-αβ receptor blockers or antagonists should be considered as an option to prevent exuberant inflammatory responses during later stages of severe disease, particularly during SARS [<xref ref-type="bibr" rid="CR38">38</xref>]. In contrast to IFN-αβ, IFN-λ mainly activates epithelial cells and lacks monocyte-macrophage-mediated pro-inflammatory activity of IFN-αβ [<xref ref-type="bibr" rid="CR123">123</xref>]. Additionally, IFN-λ suppresses neutrophil recruitment to the site of inflammation [<xref ref-type="bibr" rid="CR124">124</xref>]. Since SARS-CoV and MERS-CoV predominantly infect AECs and IFN-λ stimulates antiviral gene in epithelial cells without over-stimulating the immune system, use of IFN-λ may be an ideal therapeutic option.</p></sec><sec id="FPar6"><title>Suppression of oxidized phospholipids</title><p id="Par35">Oxidized phospholipids (OxPL) have been shown to promote ALI by increasing lung macrophage cytokine/chemokine production via TLR4-TRIF signaling in influenza A virus (IAV)-infected mice [<xref ref-type="bibr" rid="CR125">125</xref>]. In a recent study, therapeutic administration of the TLR4 antagonist, Eritoran, protected mice from lethal IAV infection by reducing the levels of OxPL and inflammatory cytokines and chemokines [<xref ref-type="bibr" rid="CR126">126</xref>]. Despite potent immunomodulatory functions, Eritoran has no direct antiviral activity, suggesting its use in the amelioration of inflammatory responses. Since pathogenic human coronaviruses cause acute lung injury and promote OxPL production in the lungs [<xref ref-type="bibr" rid="CR125">125</xref>], strategies to suppress OxPL either by using Eritoran or other similar compounds could be of value in dampening hCoV-induced inflammation.</p></sec><sec id="FPar7"><title>Sphingosine-1-phosphate receptor 1 agonist therapy</title><p id="Par36">In mice infected with IAV, sphingosine-1-phosphate receptor 1 (S1P1) signaling in endothelial cells was shown to orchestrate pathogenic inflammatory responses [<xref ref-type="bibr" rid="CR127">127</xref>]. Targeted S1P1 agonism restrained excessive inflammatory cell recruitment, suppressed pro-inflammatory cytokines and chemokines, and reduced IAV induced morbidity and mortality [<xref ref-type="bibr" rid="CR127">127</xref>, <xref ref-type="bibr" rid="CR128">128</xref>]. SARS-CoV infects lung epithelial cells and endothelial cells in humans and NHPs [<xref ref-type="bibr" rid="CR29">29</xref>], so that SARS-CoV infection of endothelial cells may drive S1P1-mediated inflammatory cytokine/chemokine responses and neutrophil and macrophage accumulation. Therefore, S1P1 agonism could be a potential therapeutic agent in hCoV patients to dampen pathogenic cytokine and chemokine responses, if a role for an excessive immune response by these cells is demonstrated.</p></sec><sec id="FPar8"><title>Inhibitors of monocyte recruitment and function</title><p id="Par37">Studies in animal models demonstrate pathogenic roles for IMMs during lethal hCoV infections. In a mouse model of cardiac inflammation, systemic delivery of optimized lipid nanoparticles containing a CCR2-silencing short interfering RNA (siRNA) efficiently degraded CCR2 mRNA and impaired IMM recruitment to sites of inflammation thus resulting in improved disease outcome [<xref ref-type="bibr" rid="CR129">129</xref>, <xref ref-type="bibr" rid="CR130">130</xref>]. Since hCoVs are single-stranded RNA (ssRNA) viruses and stimulation of IMMs with the TLR7 agonist, R837 (a synthetic ssRNA mimic), induces strong inflammatory responses, it is possible that IMM-specific TLR-7 signaling promotes excessive inflammation in response to hCoV infection. Thus, a TLR7 antagonist-targeted approach to mitigate inflammation could prove beneficial.</p></sec><sec id="FPar9"><title>Other immunomodulatory agents</title><p id="Par38">Several other immunomodulatory agents that could ameliorate inflammatory responses following pathogenic hCoV infections include cytokine/chemokine inhibitors and danger-associated molecular pattern (DAMP) antagonists [<xref ref-type="bibr" rid="CR131">131</xref>]. Studies from animal models show a significant contribution of TNF to acute lung injury and impaired T cell responses in SARS-CoV-challenged mice. In vivo neutralization of TNF activity or infection of mice lacking TNFR provides protection against SARS-CoV-induced morbidity and mortality [<xref ref-type="bibr" rid="CR38">38</xref>, <xref ref-type="bibr" rid="CR132">132</xref>]. However, it is to be noted that TNF was not detected in the serum of SARS patients at least during later stages of infection.</p></sec></sec></sec><sec id="Sec18"><title>Conclusion</title><p id="Par39">Inflammation is an indispensable part of an effective immune response, without which successful elimination of an infectious agent is difficult. The inflammatory response begins with the initial recognition of a pathogen, which then mediates immune cell recruitment, eliminates pathogens, and ultimately results in tissue repair and return to homeostasis. However, certain viruses such as highly pathogenic CoVs, IAV, and ebola viruses induce excessive and prolonged cytokine/chemokine response known as “cytokine storms,” which results in high morbidity and mortality due to immunopathology. Although studies reviewed in this manuscript provide evidence that “cytokine storms” and immunopathology can occur during pathogenic hCOV infections, we do not yet have a sufficient understanding of the specific factor/s responsible for exuberant inflammatory responses. Studies from human autopsies and animal models strongly suggest a pathogenic role for inflammatory cytokines/chemokines derived from IMM and neutrophils. Therefore, therapeutic interventions targeting these pro-inflammatory cytokines and chemokines could prove beneficial in ameliorating undesirable inflammatory responses. Additionally, since high virus titers at early and later stages of infection strongly correlate with disease severity in humans, strategies directed at controlling viral load as well as attenuating the inflammatory response might prove beneficial. Therefore, future studies should focus on identification of specific signaling pathways that mediate inflammatory responses in hCoV-infected patients and animals.</p></sec></body><back><ack><title>Acknowledgements</title><p>We thank Dr. Anthony Fehr for careful review of this manuscript. This work was supported in part by grants from the N.I.H. (PO1 AI060699, RO1 AI091322).</p></ack><ref-list id="Bib1"><title>References</title><ref id="CR1"><label>1.</label><mixed-citation publication-type="other">Masters PS, Perlman, S (2013) Coronaviridae. In: Knipe DM, Howley P (eds) Fields Virology. Lippincott Williams and Wilkins, Philadelphia, PA, pp 825–858</mixed-citation></ref><ref id="CR2"><label>2.</label><element-citation publication-type="book"><person-group person-group-type="author"><name><surname>Siddell</surname><given-names>SZJ</given-names></name><name><surname>Snijder</surname><given-names>EJ</given-names></name></person-group><source>Coronaviruses, toroviruses, and arteriviruses, vol. 1</source><year>2005</year><publisher-loc>London</publisher-loc><publisher-name>Hodder Arnold</publisher-name></element-citation></ref><ref id="CR3"><label>3.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Peck</surname><given-names>KM</given-names></name><etal></etal></person-group><article-title>Coronavirus host range expansion and Middle East respiratory syndrome coronavirus emergence: biochemical mechanisms and evolutionary perspectives</article-title><source>Annu Rev Virol</source><year>2015</year><volume>2</volume><issue>1</issue><fpage>95</fpage><lpage>117</lpage><pub-id pub-id-type="doi">10.1146/annurev-virology-100114-055029</pub-id><pub-id pub-id-type="pmid">26958908</pub-id></element-citation></ref><ref id="CR4"><label>4.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Su</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>Epidemiology, genetic recombination, and pathogenesis of coronaviruses</article-title><source>Trends Microbiol</source><year>2016</year><volume>24</volume><issue>6</issue><fpage>490</fpage><lpage>502</lpage><pub-id pub-id-type="doi">10.1016/j.tim.2016.03.003</pub-id><pub-id pub-id-type="pmid">27012512</pub-id></element-citation></ref><ref id="CR5"><label>5.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Weiss</surname><given-names>SR</given-names></name><name><surname>Navas-Martin</surname><given-names>S</given-names></name></person-group><article-title>Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus</article-title><source>Microbiol Mol Biol Rev</source><year>2005</year><volume>69</volume><issue>4</issue><fpage>635</fpage><lpage>664</lpage><pub-id pub-id-type="doi">10.1128/MMBR.69.4.635-664.2005</pub-id><pub-id pub-id-type="pmid">16339739</pub-id></element-citation></ref><ref id="CR6"><label>6.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Heugel</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Coronavirus-associated pneumonia in previously healthy children</article-title><source>Pediatr Infect Dis J</source><year>2007</year><volume>26</volume><issue>8</issue><fpage>753</fpage><lpage>755</lpage><pub-id pub-id-type="doi">10.1097/INF.0b013e318054e31b</pub-id><pub-id pub-id-type="pmid">17848893</pub-id></element-citation></ref><ref id="CR7"><label>7.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kuypers</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Clinical disease in children associated with newly described coronavirus subtypes</article-title><source>Pediatrics</source><year>2007</year><volume>119</volume><issue>1</issue><fpage>e70</fpage><lpage>e76</lpage><pub-id pub-id-type="doi">10.1542/peds.2006-1406</pub-id><pub-id pub-id-type="pmid">17130280</pub-id></element-citation></ref><ref id="CR8"><label>8.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Drosten</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>Identification of a novel coronavirus in patients with severe acute respiratory syndrome</article-title><source>N Engl J Med</source><year>2003</year><volume>348</volume><issue>20</issue><fpage>1967</fpage><lpage>1976</lpage><pub-id pub-id-type="doi">10.1056/NEJMoa030747</pub-id><pub-id pub-id-type="pmid">12690091</pub-id></element-citation></ref><ref id="CR9"><label>9.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kuiken</surname><given-names>T</given-names></name><etal></etal></person-group><article-title>Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome</article-title><source>Lancet</source><year>2003</year><volume>362</volume><issue>9380</issue><fpage>263</fpage><lpage>270</lpage><pub-id pub-id-type="doi">10.1016/S0140-6736(03)13967-0</pub-id><pub-id pub-id-type="pmid">12892955</pub-id></element-citation></ref><ref id="CR10"><label>10.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Peiris</surname><given-names>JS</given-names></name><etal></etal></person-group><article-title>Coronavirus as a possible cause of severe acute respiratory syndrome</article-title><source>Lancet</source><year>2003</year><volume>361</volume><issue>9366</issue><fpage>1319</fpage><lpage>1325</lpage><pub-id pub-id-type="doi">10.1016/S0140-6736(03)13077-2</pub-id><pub-id pub-id-type="pmid">12711465</pub-id></element-citation></ref><ref id="CR11"><label>11.</label><mixed-citation publication-type="other">van Boheemen S et al (2012) Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans. MBio 3(6)</mixed-citation></ref><ref id="CR12"><label>12.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zaki</surname><given-names>AM</given-names></name><etal></etal></person-group><article-title>Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia</article-title><source>N Engl J Med</source><year>2012</year><volume>367</volume><issue>19</issue><fpage>1814</fpage><lpage>1820</lpage><pub-id pub-id-type="doi">10.1056/NEJMoa1211721</pub-id><pub-id pub-id-type="pmid">23075143</pub-id></element-citation></ref><ref id="CR13"><label>13.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Perlman</surname><given-names>S</given-names></name><name><surname>Netland</surname><given-names>J</given-names></name></person-group><article-title>Coronaviruses post-SARS: update on replication and pathogenesis</article-title><source>Nat Rev Microbiol</source><year>2009</year><volume>7</volume><issue>6</issue><fpage>439</fpage><lpage>450</lpage><pub-id pub-id-type="doi">10.1038/nrmicro2147</pub-id><pub-id pub-id-type="pmid">19430490</pub-id></element-citation></ref><ref id="CR14"><label>14.</label><mixed-citation publication-type="other">WHO Cumulative number of reported probable cases of SARS. In: 2003</mixed-citation></ref><ref id="CR15"><label>15.</label><mixed-citation publication-type="other"><ext-link ext-link-type="uri" xlink:href="http://www.who.int/csr/disease/coronavirus_infections/MERS_CoV_RA_20140613.pdf">http://www.who.int/csr/disease/coronavirus_infections/MERS_CoV_RA_20140613.pdf</ext-link> WUoM-CTfAtHaIRfA-RGLaoMAf</mixed-citation></ref><ref id="CR16"><label>16.</label><mixed-citation publication-type="other">WHO: Middle East respiratory syndrome coronavirus (MERS-CoV). <ext-link ext-link-type="uri" xlink:href="http://www.who.int/emergencies/mers-cov/en/">http://www.who.int/emergencies/mers-cov/en/</ext-link></mixed-citation></ref><ref id="CR17"><label>17.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Adney</surname><given-names>DR</given-names></name><etal></etal></person-group><article-title>Replication and shedding of MERS-CoV in upper respiratory tract of inoculated dromedary camels</article-title><source>Emerg Infect Dis</source><year>2014</year><volume>20</volume><issue>12</issue><fpage>1999</fpage><lpage>2005</lpage><pub-id pub-id-type="doi">10.3201/eid2012.141280</pub-id><pub-id pub-id-type="pmid">25418529</pub-id></element-citation></ref><ref id="CR18"><label>18.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Alagaili</surname><given-names>AN</given-names></name><etal></etal></person-group><article-title>Middle East respiratory syndrome coronavirus infection in dromedary camels in Saudi Arabia</article-title><source>MBio</source><year>2014</year><volume>5</volume><issue>2</issue><fpage>e00884</fpage><lpage>e00814</lpage><pub-id pub-id-type="doi">10.1128/mBio.00884-14</pub-id><pub-id pub-id-type="pmid">24570370</pub-id></element-citation></ref><ref id="CR19"><label>19.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ge</surname><given-names>XY</given-names></name><etal></etal></person-group><article-title>Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor</article-title><source>Nature</source><year>2013</year><volume>503</volume><issue>7477</issue><fpage>535</fpage><lpage>538</lpage><pub-id pub-id-type="doi">10.1038/nature12711</pub-id><pub-id pub-id-type="pmid">24172901</pub-id></element-citation></ref><ref id="CR20"><label>20.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Menachery</surname><given-names>VD</given-names></name><etal></etal></person-group><article-title>A SARS-like cluster of circulating bat coronaviruses shows potential for human emergence</article-title><source>Nat Med</source><year>2015</year><volume>21</volume><issue>12</issue><fpage>1508</fpage><lpage>1513</lpage><pub-id pub-id-type="doi">10.1038/nm.3985</pub-id><pub-id pub-id-type="pmid">26552008</pub-id></element-citation></ref><ref id="CR21"><label>21.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Arabi</surname><given-names>YM</given-names></name><etal></etal></person-group><article-title>Clinical course and outcomes of critically ill patients with Middle East respiratory syndrome coronavirus infection</article-title><source>Ann Intern Med</source><year>2014</year><volume>160</volume><issue>6</issue><fpage>389</fpage><lpage>397</lpage><pub-id pub-id-type="doi">10.7326/M13-2486</pub-id><pub-id pub-id-type="pmid">24474051</pub-id></element-citation></ref><ref id="CR22"><label>22.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Assiri</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study</article-title><source>Lancet Infect Dis</source><year>2013</year><volume>13</volume><issue>9</issue><fpage>752</fpage><lpage>761</lpage><pub-id pub-id-type="doi">10.1016/S1473-3099(13)70204-4</pub-id><pub-id pub-id-type="pmid">23891402</pub-id></element-citation></ref><ref id="CR23"><label>23.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Leong</surname><given-names>HN</given-names></name><etal></etal></person-group><article-title>Clinical and laboratory findings of SARS in Singapore</article-title><source>Ann Acad Med Singap</source><year>2006</year><volume>35</volume><issue>5</issue><fpage>332</fpage><lpage>339</lpage><pub-id pub-id-type="pmid">16830000</pub-id></element-citation></ref><ref id="CR24"><label>24.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Saad</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Clinical aspects and outcomes of 70 patients with Middle East respiratory syndrome coronavirus infection: a single-center experience in Saudi Arabia</article-title><source>Int J Infect Dis</source><year>2014</year><volume>29</volume><fpage>301</fpage><lpage>306</lpage><pub-id pub-id-type="doi">10.1016/j.ijid.2014.09.003</pub-id><pub-id pub-id-type="pmid">25303830</pub-id></element-citation></ref><ref id="CR25"><label>25.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Al-Tawfiq</surname><given-names>JA</given-names></name><etal></etal></person-group><article-title>Middle East respiratory syndrome coronavirus: a case-control study of hospitalized patients</article-title><source>Clin Infect Dis</source><year>2014</year><volume>59</volume><issue>2</issue><fpage>160</fpage><lpage>165</lpage><pub-id pub-id-type="doi">10.1093/cid/ciu226</pub-id><pub-id pub-id-type="pmid">24723278</pub-id></element-citation></ref><ref id="CR26"><label>26.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zumla</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Middle East respiratory syndrome</article-title><source>Lancet</source><year>2015</year><volume>386</volume><issue>9997</issue><fpage>995</fpage><lpage>1007</lpage><pub-id pub-id-type="doi">10.1016/S0140-6736(15)60454-8</pub-id><pub-id pub-id-type="pmid">26049252</pub-id></element-citation></ref><ref id="CR27"><label>27.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Peiris</surname><given-names>JS</given-names></name><etal></etal></person-group><article-title>Severe acute respiratory syndrome</article-title><source>Nat Med</source><year>2004</year><volume>10</volume><issue>12 Suppl</issue><fpage>S88</fpage><lpage>S97</lpage><pub-id pub-id-type="doi">10.1038/nm1143</pub-id><pub-id pub-id-type="pmid">15577937</pub-id></element-citation></ref><ref id="CR28"><label>28.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Peiris</surname><given-names>JS</given-names></name><etal></etal></person-group><article-title>Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study</article-title><source>Lancet</source><year>2003</year><volume>361</volume><issue>9371</issue><fpage>1767</fpage><lpage>1772</lpage><pub-id pub-id-type="doi">10.1016/S0140-6736(03)13412-5</pub-id><pub-id pub-id-type="pmid">12781535</pub-id></element-citation></ref><ref id="CR29"><label>29.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nicholls</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>SARS: clinical virology and pathogenesis</article-title><source>Respirology</source><year>2003</year><volume>8</volume><issue>Suppl</issue><fpage>S6</fpage><lpage>S8</lpage><pub-id pub-id-type="doi">10.1046/j.1440-1843.2003.00517.x</pub-id><pub-id pub-id-type="pmid">15018126</pub-id></element-citation></ref><ref id="CR30"><label>30.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>van den Brand</surname><given-names>JM</given-names></name><etal></etal></person-group><article-title>The pathology and pathogenesis of experimental severe acute respiratory syndrome and influenza in animal models</article-title><source>J Comp Pathol</source><year>2014</year><volume>151</volume><issue>1</issue><fpage>83</fpage><lpage>112</lpage><pub-id pub-id-type="doi">10.1016/j.jcpa.2014.01.004</pub-id><pub-id pub-id-type="pmid">24581932</pub-id></element-citation></ref><ref id="CR31"><label>31.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gu</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Multiple organ infection and the pathogenesis of SARS</article-title><source>J Exp Med</source><year>2005</year><volume>202</volume><issue>3</issue><fpage>415</fpage><lpage>424</lpage><pub-id pub-id-type="doi">10.1084/jem.20050828</pub-id><pub-id pub-id-type="pmid">16043521</pub-id></element-citation></ref><ref id="CR32"><label>32.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nicholls</surname><given-names>JM</given-names></name><etal></etal></person-group><article-title>Lung pathology of fatal severe acute respiratory syndrome</article-title><source>Lancet</source><year>2003</year><volume>361</volume><issue>9371</issue><fpage>1773</fpage><lpage>1778</lpage><pub-id pub-id-type="doi">10.1016/S0140-6736(03)13413-7</pub-id><pub-id pub-id-type="pmid">12781536</pub-id></element-citation></ref><ref id="CR33"><label>33.</label><mixed-citation publication-type="other">van den Brand JM et al (2014) The pathology and pathogenesis of experimental severe acute respiratory syndrome and influenza in animal models. J Comp Pathol 151(1):83–112</mixed-citation></ref><ref id="CR34"><label>34.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cui</surname><given-names>W</given-names></name><etal></etal></person-group><article-title>Expression of lymphocytes and lymphocyte subsets in patients with severe acute respiratory syndrome</article-title><source>Clin Infect Dis</source><year>2003</year><volume>37</volume><issue>6</issue><fpage>857</fpage><lpage>859</lpage><pub-id pub-id-type="doi">10.1086/378587</pub-id><pub-id pub-id-type="pmid">12955652</pub-id></element-citation></ref><ref id="CR35"><label>35.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Li</surname><given-names>T</given-names></name><etal></etal></person-group><article-title>Significant changes of peripheral T lymphocyte subsets in patients with severe acute respiratory syndrome</article-title><source>J Infect Dis</source><year>2004</year><volume>189</volume><issue>4</issue><fpage>648</fpage><lpage>651</lpage><pub-id pub-id-type="doi">10.1086/381535</pub-id><pub-id pub-id-type="pmid">14767818</pub-id></element-citation></ref><ref id="CR36"><label>36.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname><given-names>YH</given-names></name><etal></etal></person-group><article-title>A cluster of patients with severe acute respiratory syndrome in a chest ward in southern Taiwan</article-title><source>Intensive Care Med</source><year>2004</year><volume>30</volume><issue>6</issue><fpage>1228</fpage><lpage>1231</lpage><pub-id pub-id-type="doi">10.1007/s00134-004-2311-8</pub-id><pub-id pub-id-type="pmid">15105985</pub-id></element-citation></ref><ref id="CR37"><label>37.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ng</surname><given-names>DL</given-names></name><etal></etal></person-group><article-title>Clinicopathologic, immunohistochemical, and ultrastructural findings of a fatal case of Middle East respiratory syndrome coronavirus infection in the United Arab Emirates, April 2014</article-title><source>Am J Pathol</source><year>2016</year><volume>186</volume><issue>3</issue><fpage>652</fpage><lpage>658</lpage><pub-id pub-id-type="doi">10.1016/j.ajpath.2015.10.024</pub-id><pub-id pub-id-type="pmid">26857507</pub-id></element-citation></ref><ref id="CR38"><label>38.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Channappanavar</surname><given-names>R</given-names></name><etal></etal></person-group><article-title>Dysregulated type I interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in SARS-CoV-infected mice</article-title><source>Cell Host Microbe</source><year>2016</year><volume>19</volume><issue>2</issue><fpage>181</fpage><lpage>193</lpage><pub-id pub-id-type="doi">10.1016/j.chom.2016.01.007</pub-id><pub-id pub-id-type="pmid">26867177</pub-id></element-citation></ref><ref id="CR39"><label>39.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Davidson</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>Disease-promoting effects of type I interferons in viral, bacterial, and coinfections</article-title><source>J Interf Cytokine Res</source><year>2015</year><volume>35</volume><issue>4</issue><fpage>252</fpage><lpage>264</lpage><pub-id pub-id-type="doi">10.1089/jir.2014.0227</pub-id></element-citation></ref><ref id="CR40"><label>40.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Shaw</surname><given-names>AC</given-names></name><etal></etal></person-group><article-title>Age-dependent dysregulation of innate immunity</article-title><source>Nat Rev Immunol</source><year>2013</year><volume>13</volume><issue>12</issue><fpage>875</fpage><lpage>887</lpage><pub-id pub-id-type="doi">10.1038/nri3547</pub-id><pub-id pub-id-type="pmid">24157572</pub-id></element-citation></ref><ref id="CR41"><label>41.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cheung</surname><given-names>CY</given-names></name><etal></etal></person-group><article-title>Cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: possible relevance to pathogenesis</article-title><source>J Virol</source><year>2005</year><volume>79</volume><issue>12</issue><fpage>7819</fpage><lpage>7826</lpage><pub-id pub-id-type="doi">10.1128/JVI.79.12.7819-7826.2005</pub-id><pub-id pub-id-type="pmid">15919935</pub-id></element-citation></ref><ref id="CR42"><label>42.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Law</surname><given-names>HK</given-names></name><etal></etal></person-group><article-title>Chemokine up-regulation in SARS-coronavirus-infected, monocyte-derived human dendritic cells</article-title><source>Blood</source><year>2005</year><volume>106</volume><issue>7</issue><fpage>2366</fpage><lpage>2374</lpage><pub-id pub-id-type="doi">10.1182/blood-2004-10-4166</pub-id><pub-id pub-id-type="pmid">15860669</pub-id></element-citation></ref><ref id="CR43"><label>43.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yen</surname><given-names>YT</given-names></name><etal></etal></person-group><article-title>Modeling the early events of severe acute respiratory syndrome coronavirus infection in vitro</article-title><source>J Virol</source><year>2006</year><volume>80</volume><issue>6</issue><fpage>2684</fpage><lpage>2693</lpage><pub-id pub-id-type="doi">10.1128/JVI.80.6.2684-2693.2006</pub-id><pub-id pub-id-type="pmid">16501078</pub-id></element-citation></ref><ref id="CR44"><label>44.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chien</surname><given-names>JY</given-names></name><etal></etal></person-group><article-title>Temporal changes in cytokine/chemokine profiles and pulmonary involvement in severe acute respiratory syndrome</article-title><source>Respirology</source><year>2006</year><volume>11</volume><issue>6</issue><fpage>715</fpage><lpage>722</lpage><pub-id pub-id-type="doi">10.1111/j.1440-1843.2006.00942.x</pub-id><pub-id pub-id-type="pmid">17052299</pub-id></element-citation></ref><ref id="CR45"><label>45.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname><given-names>CH</given-names></name><etal></etal></person-group><article-title>Persistence of lung inflammation and lung cytokines with high-resolution CT abnormalities during recovery from SARS</article-title><source>Respir Res</source><year>2005</year><volume>6</volume><fpage>42</fpage><pub-id pub-id-type="doi">10.1186/1465-9921-6-42</pub-id><pub-id pub-id-type="pmid">15888207</pub-id></element-citation></ref><ref id="CR46"><label>46.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wong</surname><given-names>CK</given-names></name><etal></etal></person-group><article-title>Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome</article-title><source>Clin Exp Immunol</source><year>2004</year><volume>136</volume><issue>1</issue><fpage>95</fpage><lpage>103</lpage><pub-id pub-id-type="doi">10.1111/j.1365-2249.2004.02415.x</pub-id><pub-id pub-id-type="pmid">15030519</pub-id></element-citation></ref><ref id="CR47"><label>47.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zhang</surname><given-names>Y</given-names></name><etal></etal></person-group><article-title>Analysis of serum cytokines in patients with severe acute respiratory syndrome</article-title><source>Infect Immun</source><year>2004</year><volume>72</volume><issue>8</issue><fpage>4410</fpage><lpage>4415</lpage><pub-id pub-id-type="doi">10.1128/IAI.72.8.4410-4415.2004</pub-id><pub-id pub-id-type="pmid">15271897</pub-id></element-citation></ref><ref id="CR48"><label>48.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cameron</surname><given-names>MJ</given-names></name><etal></etal></person-group><article-title>Human immunopathogenesis of severe acute respiratory syndrome (SARS)</article-title><source>Virus Res</source><year>2008</year><volume>133</volume><issue>1</issue><fpage>13</fpage><lpage>19</lpage><pub-id pub-id-type="doi">10.1016/j.virusres.2007.02.014</pub-id><pub-id pub-id-type="pmid">17374415</pub-id></element-citation></ref><ref id="CR49"><label>49.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cameron</surname><given-names>MJRL</given-names></name><name><surname>Xu</surname><given-names>L</given-names></name><name><surname>Danesh</surname><given-names>A</given-names></name><name><surname>Bermejo-Martin</surname><given-names>JF</given-names></name><name><surname>Cameron</surname><given-names>CM</given-names></name><name><surname>Muller</surname><given-names>MP</given-names></name><name><surname>Gold</surname><given-names>WL</given-names></name><name><surname>Richardson</surname><given-names>SE</given-names></name><name><surname>Poutanen</surname><given-names>SM</given-names></name><name><surname>Willey</surname><given-names>BM</given-names></name><name><surname>DeVries</surname><given-names>ME</given-names></name><name><surname>Fang</surname><given-names>Y</given-names></name><name><surname>Seneviratne</surname><given-names>C</given-names></name><name><surname>Bosinger</surname><given-names>SE</given-names></name><name><surname>Persad</surname><given-names>D</given-names></name><name><surname>Keshavjee</surname><given-names>S</given-names></name><name><surname>Louie</surname><given-names>M</given-names></name><name><surname>Loeb</surname><given-names>MB</given-names></name><name><surname>Brunton</surname><given-names>J</given-names></name><name><surname>McGeer</surname><given-names>AJ</given-names></name><name><surname>Kelvin</surname><given-names>DJ</given-names></name></person-group><article-title>Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome</article-title><source>J Virol</source><year>2007</year><volume>81</volume><issue>16</issue><fpage>8692</fpage><lpage>8706</lpage><pub-id pub-id-type="doi">10.1128/JVI.00527-07</pub-id><pub-id pub-id-type="pmid">17537853</pub-id></element-citation></ref><ref id="CR50"><label>50.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Huang</surname><given-names>KJ</given-names></name><etal></etal></person-group><article-title>An interferon-gamma-related cytokine storm in SARS patients</article-title><source>J Med Virol</source><year>2005</year><volume>75</volume><issue>2</issue><fpage>185</fpage><lpage>194</lpage><pub-id pub-id-type="doi">10.1002/jmv.20255</pub-id><pub-id pub-id-type="pmid">15602737</pub-id></element-citation></ref><ref id="CR51"><label>51.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Theron</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>A probable role for IFN-gamma in the development of a lung immunopathology in SARS</article-title><source>Cytokine</source><year>2005</year><volume>32</volume><issue>1</issue><fpage>30</fpage><lpage>38</lpage><pub-id pub-id-type="doi">10.1016/j.cyto.2005.07.007</pub-id><pub-id pub-id-type="pmid">16129616</pub-id></element-citation></ref><ref id="CR52"><label>52.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lau</surname><given-names>SK</given-names></name><etal></etal></person-group><article-title>Delayed induction of proinflammatory cytokines and suppression of innate antiviral response by the novel Middle East respiratory syndrome coronavirus: implications for pathogenesis and treatment</article-title><source>J Gen Virol</source><year>2013</year><volume>94</volume><issue>Pt 12</issue><fpage>2679</fpage><lpage>2690</lpage><pub-id pub-id-type="doi">10.1099/vir.0.055533-0</pub-id><pub-id pub-id-type="pmid">24077366</pub-id></element-citation></ref><ref id="CR53"><label>53.</label><mixed-citation publication-type="other">Chu H et al (2015) Middle East respiratory syndrome coronavirus efficiently infects human primary T lymphocytes and activates the extrinsic and intrinsic apoptosis pathways. J Infect Dis 213(6):904–14</mixed-citation></ref><ref id="CR54"><label>54.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tynell</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Middle East respiratory syndrome coronavirus shows poor replication but significant induction of antiviral responses in human monocyte-derived macrophages and dendritic cells</article-title><source>J Gen Virol</source><year>2016</year><volume>97</volume><issue>2</issue><fpage>344</fpage><lpage>355</lpage><pub-id pub-id-type="doi">10.1099/jgv.0.000351</pub-id><pub-id pub-id-type="pmid">26602089</pub-id></element-citation></ref><ref id="CR55"><label>55.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zhou</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Active replication of Middle East respiratory syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages: implications for pathogenesis</article-title><source>J Infect Dis</source><year>2014</year><volume>209</volume><issue>9</issue><fpage>1331</fpage><lpage>1342</lpage><pub-id pub-id-type="doi">10.1093/infdis/jit504</pub-id><pub-id pub-id-type="pmid">24065148</pub-id></element-citation></ref><ref id="CR56"><label>56.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Scheuplein</surname><given-names>VA</given-names></name><etal></etal></person-group><article-title>High secretion of interferons by human plasmacytoid dendritic cells upon recognition of Middle East respiratory syndrome coronavirus</article-title><source>J Virol</source><year>2015</year><volume>89</volume><issue>7</issue><fpage>3859</fpage><lpage>3869</lpage><pub-id pub-id-type="doi">10.1128/JVI.03607-14</pub-id><pub-id pub-id-type="pmid">25609809</pub-id></element-citation></ref><ref id="CR57"><label>57.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kim</surname><given-names>ES</given-names></name><etal></etal></person-group><article-title>Clinical progression and cytokine profiles of Middle East respiratory syndrome coronavirus infection</article-title><source>J Korean Med Sci</source><year>2016</year><volume>31</volume><issue>11</issue><fpage>1717</fpage><lpage>1725</lpage><pub-id pub-id-type="doi">10.3346/jkms.2016.31.11.1717</pub-id><pub-id pub-id-type="pmid">27709848</pub-id></element-citation></ref><ref id="CR58"><label>58.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Min</surname><given-names>CK</given-names></name><etal></etal></person-group><article-title>Comparative and kinetic analysis of viral shedding and immunological responses in MERS patients representing a broad spectrum of disease severity</article-title><source>Sci Rep</source><year>2016</year><volume>6</volume><fpage>25359</fpage><pub-id pub-id-type="doi">10.1038/srep25359</pub-id><pub-id pub-id-type="pmid">27146253</pub-id></element-citation></ref><ref id="CR59"><label>59.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Roberts</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Aged BALB/c mice as a model for increased severity of severe acute respiratory syndrome in elderly humans</article-title><source>J Virol</source><year>2005</year><volume>79</volume><issue>9</issue><fpage>5833</fpage><lpage>5838</lpage><pub-id pub-id-type="doi">10.1128/JVI.79.9.5833-5838.2005</pub-id><pub-id pub-id-type="pmid">15827197</pub-id></element-citation></ref><ref id="CR60"><label>60.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Day</surname><given-names>CW</given-names></name><etal></etal></person-group><article-title>A new mouse-adapted strain of SARS-CoV as a lethal model for evaluating antiviral agents in vitro and in vivo</article-title><source>Virology</source><year>2009</year><volume>395</volume><issue>2</issue><fpage>210</fpage><lpage>222</lpage><pub-id pub-id-type="doi">10.1016/j.virol.2009.09.023</pub-id><pub-id pub-id-type="pmid">19853271</pub-id></element-citation></ref><ref id="CR61"><label>61.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nagata</surname><given-names>N</given-names></name><etal></etal></person-group><article-title>Mouse-passaged severe acute respiratory syndrome-associated coronavirus leads to lethal pulmonary edema and diffuse alveolar damage in adult but not young mice</article-title><source>Am J Pathol</source><year>2008</year><volume>172</volume><issue>6</issue><fpage>1625</fpage><lpage>1637</lpage><pub-id pub-id-type="doi">10.2353/ajpath.2008.071060</pub-id><pub-id pub-id-type="pmid">18467696</pub-id></element-citation></ref><ref id="CR62"><label>62.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Roberts</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>A mouse-adapted SARS-coronavirus causes disease and mortality in BALB/c mice</article-title><source>PLoS Pathog</source><year>2007</year><volume>3</volume><issue>1</issue><fpage>e5</fpage><pub-id pub-id-type="doi">10.1371/journal.ppat.0030005</pub-id><pub-id pub-id-type="pmid">17222058</pub-id></element-citation></ref><ref id="CR63"><label>63.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Frieman</surname><given-names>MB</given-names></name><etal></etal></person-group><article-title>SARS-CoV pathogenesis is regulated by a STAT1 dependent but a type I, II and III interferon receptor independent mechanism</article-title><source>PLoS Pathog</source><year>2010</year><volume>6</volume><issue>4</issue><fpage>e1000849</fpage><pub-id pub-id-type="doi">10.1371/journal.ppat.1000849</pub-id><pub-id pub-id-type="pmid">20386712</pub-id></element-citation></ref><ref id="CR64"><label>64.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zhao</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Age-related increases in PGD(2) expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice</article-title><source>J Clin Invest</source><year>2011</year><volume>121</volume><issue>12</issue><fpage>4921</fpage><lpage>4930</lpage><pub-id pub-id-type="doi">10.1172/JCI59777</pub-id><pub-id pub-id-type="pmid">22105170</pub-id></element-citation></ref><ref id="CR65"><label>65.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Graham</surname><given-names>RL</given-names></name><etal></etal></person-group><article-title>A live, impaired-fidelity coronavirus vaccine protects in an aged, immunocompromised mouse model of lethal disease</article-title><source>Nat Med</source><year>2012</year><volume>18</volume><issue>12</issue><fpage>1820</fpage><lpage>1826</lpage><pub-id pub-id-type="doi">10.1038/nm.2972</pub-id><pub-id pub-id-type="pmid">23142821</pub-id></element-citation></ref><ref id="CR66"><label>66.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rockx</surname><given-names>B</given-names></name><etal></etal></person-group><article-title>Early upregulation of acute respiratory distress syndrome-associated cytokines promotes lethal disease in an aged-mouse model of severe acute respiratory syndrome coronavirus infection</article-title><source>J Virol</source><year>2009</year><volume>83</volume><issue>14</issue><fpage>7062</fpage><lpage>7074</lpage><pub-id pub-id-type="doi">10.1128/JVI.00127-09</pub-id><pub-id pub-id-type="pmid">19420084</pub-id></element-citation></ref><ref id="CR67"><label>67.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Smits</surname><given-names>SL</given-names></name><etal></etal></person-group><article-title>Exacerbated innate host response to SARS-CoV in aged non-human primates</article-title><source>PLoS Pathog</source><year>2010</year><volume>6</volume><issue>2</issue><fpage>e1000756</fpage><pub-id pub-id-type="doi">10.1371/journal.ppat.1000756</pub-id><pub-id pub-id-type="pmid">20140198</pub-id></element-citation></ref><ref id="CR68"><label>68.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Totura</surname><given-names>AL</given-names></name><etal></etal></person-group><article-title>Toll-like receptor 3 signaling via TRIF contributes to a protective innate immune response to severe acute respiratory syndrome coronavirus infection</article-title><source>MBio</source><year>2015</year><volume>6</volume><issue>3</issue><fpage>e00638</fpage><lpage>e00615</lpage><pub-id pub-id-type="doi">10.1128/mBio.00638-15</pub-id><pub-id pub-id-type="pmid">26015500</pub-id></element-citation></ref><ref id="CR69"><label>69.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jimenez-Guardeno</surname><given-names>JM</given-names></name><etal></etal></person-group><article-title>The PDZ-binding motif of severe acute respiratory syndrome coronavirus envelope protein is a determinant of viral pathogenesis</article-title><source>PLoS Pathog</source><year>2014</year><volume>10</volume><issue>8</issue><fpage>e1004320</fpage><pub-id pub-id-type="doi">10.1371/journal.ppat.1004320</pub-id><pub-id pub-id-type="pmid">25122212</pub-id></element-citation></ref><ref id="CR70"><label>70.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nieto-Torres</surname><given-names>JL</given-names></name><etal></etal></person-group><article-title>Severe acute respiratory syndrome coronavirus envelope protein ion channel activity promotes virus fitness and pathogenesis</article-title><source>PLoS Pathog</source><year>2014</year><volume>10</volume><issue>5</issue><fpage>e1004077</fpage><pub-id pub-id-type="doi">10.1371/journal.ppat.1004077</pub-id><pub-id pub-id-type="pmid">24788150</pub-id></element-citation></ref><ref id="CR71"><label>71.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nieto-Torres</surname><given-names>JL</given-names></name><etal></etal></person-group><article-title>Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome</article-title><source>Virology</source><year>2015</year><volume>485</volume><fpage>330</fpage><lpage>339</lpage><pub-id pub-id-type="doi">10.1016/j.virol.2015.08.010</pub-id><pub-id pub-id-type="pmid">26331680</pub-id></element-citation></ref><ref id="CR72"><label>72.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>de Wit</surname><given-names>E</given-names></name><etal></etal></person-group><article-title>Middle East respiratory syndrome coronavirus (MERS-CoV) causes transient lower respiratory tract infection in rhesus macaques</article-title><source>Proc Natl Acad Sci U S A</source><year>2013</year><volume>110</volume><issue>41</issue><fpage>16598</fpage><lpage>16603</lpage><pub-id pub-id-type="doi">10.1073/pnas.1310744110</pub-id><pub-id pub-id-type="pmid">24062443</pub-id></element-citation></ref><ref id="CR73"><label>73.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Haagmans</surname><given-names>BL</given-names></name><etal></etal></person-group><article-title>Asymptomatic Middle East respiratory syndrome coronavirus infection in rabbits</article-title><source>J Virol</source><year>2015</year><volume>89</volume><issue>11</issue><fpage>6131</fpage><lpage>6135</lpage><pub-id pub-id-type="doi">10.1128/JVI.00661-15</pub-id><pub-id pub-id-type="pmid">25810539</pub-id></element-citation></ref><ref id="CR74"><label>74.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Houser</surname><given-names>KV</given-names></name><etal></etal></person-group><article-title>Prophylaxis with a Middle East respiratory syndrome coronavirus (MERS-CoV)-specific human monoclonal antibody protects rabbits from MERS-CoV infection</article-title><source>J Infect Dis</source><year>2016</year><volume>213</volume><issue>10</issue><fpage>1557</fpage><lpage>1561</lpage><pub-id pub-id-type="doi">10.1093/infdis/jiw080</pub-id><pub-id pub-id-type="pmid">26941283</pub-id></element-citation></ref><ref id="CR75"><label>75.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Falzarano</surname><given-names>D</given-names></name><etal></etal></person-group><article-title>Infection with MERS-CoV causes lethal pneumonia in the common marmoset</article-title><source>PLoS Pathog</source><year>2014</year><volume>10</volume><issue>8</issue><fpage>e1004250</fpage><pub-id pub-id-type="doi">10.1371/journal.ppat.1004250</pub-id><pub-id pub-id-type="pmid">25144235</pub-id></element-citation></ref><ref id="CR76"><label>76.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Johnson</surname><given-names>RF</given-names></name><etal></etal></person-group><article-title>Intratracheal exposure of common marmosets to MERS-CoV Jordan-n3/2012 or MERS-CoV EMC/2012 isolates does not result in lethal disease</article-title><source>Virology</source><year>2015</year><volume>485</volume><fpage>422</fpage><lpage>430</lpage><pub-id pub-id-type="doi">10.1016/j.virol.2015.07.013</pub-id><pub-id pub-id-type="pmid">26342468</pub-id></element-citation></ref><ref id="CR77"><label>77.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Barlan</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Receptor variation and susceptibility to Middle East respiratory syndrome coronavirus infection</article-title><source>J Virol</source><year>2014</year><volume>88</volume><issue>9</issue><fpage>4953</fpage><lpage>4961</lpage><pub-id pub-id-type="doi">10.1128/JVI.00161-14</pub-id><pub-id pub-id-type="pmid">24554656</pub-id></element-citation></ref><ref id="CR78"><label>78.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zhao</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Rapid generation of a mouse model for Middle East respiratory syndrome</article-title><source>Proc Natl Acad Sci U S A</source><year>2014</year><volume>111</volume><issue>13</issue><fpage>4970</fpage><lpage>4975</lpage><pub-id pub-id-type="doi">10.1073/pnas.1323279111</pub-id><pub-id pub-id-type="pmid">24599590</pub-id></element-citation></ref><ref id="CR79"><label>79.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gretebeck</surname><given-names>LM</given-names></name><name><surname>Subbarao</surname><given-names>K</given-names></name></person-group><article-title>Animal models for SARS and MERS coronaviruses</article-title><source>Curr Opin Virol</source><year>2015</year><volume>13</volume><fpage>123</fpage><lpage>129</lpage><pub-id pub-id-type="doi">10.1016/j.coviro.2015.06.009</pub-id><pub-id pub-id-type="pmid">26184451</pub-id></element-citation></ref><ref id="CR80"><label>80.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>van Doremalen</surname><given-names>N</given-names></name><name><surname>Munster</surname><given-names>VJ</given-names></name></person-group><article-title>Animal models of Middle East respiratory syndrome coronavirus infection</article-title><source>Antivir Res</source><year>2015</year><volume>122</volume><fpage>28</fpage><lpage>38</lpage><pub-id pub-id-type="doi">10.1016/j.antiviral.2015.07.005</pub-id><pub-id pub-id-type="pmid">26192750</pub-id></element-citation></ref><ref id="CR81"><label>81.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pascal</surname><given-names>KE</given-names></name><etal></etal></person-group><article-title>Pre- and postexposure efficacy of fully human antibodies against Spike protein in a novel humanized mouse model of MERS-CoV infection</article-title><source>Proc Natl Acad Sci U S A</source><year>2015</year><volume>112</volume><issue>28</issue><fpage>8738</fpage><lpage>8743</lpage><pub-id pub-id-type="doi">10.1073/pnas.1510830112</pub-id><pub-id pub-id-type="pmid">26124093</pub-id></element-citation></ref><ref id="CR82"><label>82.</label><mixed-citation publication-type="other">Cockrell A et al (2016) A mouse model for MERS coronavirus-induced acute respiratory distress syndrome. Nature Microbiology 2:16226</mixed-citation></ref><ref id="CR83"><label>83.</label><mixed-citation publication-type="other">Li K et al (2017) Mouse-adapted MERS coronavirus causes lethal lung disease in human DPP4 knockin mice. Proceedings of the National Academy of Sciences 114(15):E3119–E3128</mixed-citation></ref><ref id="CR84"><label>84.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Frieman</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Severe acute respiratory syndrome coronavirus ORF6 antagonizes STAT1 function by sequestering nuclear import factors on the rough endoplasmic reticulum/Golgi membrane</article-title><source>J Virol</source><year>2007</year><volume>81</volume><issue>18</issue><fpage>9812</fpage><lpage>9824</lpage><pub-id pub-id-type="doi">10.1128/JVI.01012-07</pub-id><pub-id pub-id-type="pmid">17596301</pub-id></element-citation></ref><ref id="CR85"><label>85.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kindler</surname><given-names>E</given-names></name><etal></etal></person-group><article-title>Interaction of SARS and MERS coronaviruses with the antiviral interferon response</article-title><source>Adv Virus Res</source><year>2016</year><volume>96</volume><fpage>219</fpage><lpage>243</lpage><pub-id pub-id-type="doi">10.1016/bs.aivir.2016.08.006</pub-id><pub-id pub-id-type="pmid">27712625</pub-id></element-citation></ref><ref id="CR86"><label>86.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Narayanan</surname><given-names>K</given-names></name><etal></etal></person-group><article-title>Severe acute respiratory syndrome coronavirus nsp1 suppresses host gene expression, including that of type I interferon, in infected cells</article-title><source>J Virol</source><year>2008</year><volume>82</volume><issue>9</issue><fpage>4471</fpage><lpage>4479</lpage><pub-id pub-id-type="doi">10.1128/JVI.02472-07</pub-id><pub-id pub-id-type="pmid">18305050</pub-id></element-citation></ref><ref id="CR87"><label>87.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sun</surname><given-names>L</given-names></name><etal></etal></person-group><article-title>Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling</article-title><source>PLoS One</source><year>2012</year><volume>7</volume><issue>2</issue><fpage>e30802</fpage><pub-id pub-id-type="doi">10.1371/journal.pone.0030802</pub-id><pub-id pub-id-type="pmid">22312431</pub-id></element-citation></ref><ref id="CR88"><label>88.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Thiel</surname><given-names>V</given-names></name><name><surname>Weber</surname><given-names>F</given-names></name></person-group><article-title>Interferon and cytokine responses to SARS-coronavirus infection</article-title><source>Cytokine Growth Factor Rev</source><year>2008</year><volume>19</volume><issue>2</issue><fpage>121</fpage><lpage>132</lpage><pub-id pub-id-type="doi">10.1016/j.cytogfr.2008.01.001</pub-id><pub-id pub-id-type="pmid">18321765</pub-id></element-citation></ref><ref id="CR89"><label>89.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Totura</surname><given-names>AL</given-names></name><name><surname>Baric</surname><given-names>RS</given-names></name></person-group><article-title>SARS coronavirus pathogenesis: host innate immune responses and viral antagonism of interferon</article-title><source>Current Opinion in Virology</source><year>2012</year><volume>2</volume><issue>3</issue><fpage>264</fpage><lpage>275</lpage><pub-id pub-id-type="doi">10.1016/j.coviro.2012.04.004</pub-id><pub-id pub-id-type="pmid">22572391</pub-id></element-citation></ref><ref id="CR90"><label>90.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wathelet</surname><given-names>MG</given-names></name><etal></etal></person-group><article-title>Severe acute respiratory syndrome coronavirus evades antiviral signaling: role of nsp1 and rational design of an attenuated strain</article-title><source>J Virol</source><year>2007</year><volume>81</volume><issue>21</issue><fpage>11620</fpage><lpage>11633</lpage><pub-id pub-id-type="doi">10.1128/JVI.00702-07</pub-id><pub-id pub-id-type="pmid">17715225</pub-id></element-citation></ref><ref id="CR91"><label>91.</label><mixed-citation publication-type="other">Fehr AR et al (2016) The Conserved Coronavirus Macrodomain Promotes Virulence and Suppresses the Innate Immune Response during Severe Acute Respiratory Syndrome Coronavirus Infection. mBio 7(6):e01721–16</mixed-citation></ref><ref id="CR92"><label>92.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Frieman</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Severe acute respiratory syndrome coronavirus papain-like protease ubiquitin-like domain and catalytic domain regulate antagonism of IRF3 and NF-kappaB signaling</article-title><source>J Virol</source><year>2009</year><volume>83</volume><issue>13</issue><fpage>6689</fpage><lpage>6705</lpage><pub-id pub-id-type="doi">10.1128/JVI.02220-08</pub-id><pub-id pub-id-type="pmid">19369340</pub-id></element-citation></ref><ref id="CR93"><label>93.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kopecky-Bromberg</surname><given-names>SA</given-names></name><etal></etal></person-group><article-title>Severe acute respiratory syndrome coronavirus open reading frame (ORF) 3b, ORF 6, and nucleocapsid proteins function as interferon antagonists</article-title><source>J Virol</source><year>2007</year><volume>81</volume><issue>2</issue><fpage>548</fpage><lpage>557</lpage><pub-id pub-id-type="doi">10.1128/JVI.01782-06</pub-id><pub-id pub-id-type="pmid">17108024</pub-id></element-citation></ref><ref id="CR94"><label>94.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lu</surname><given-names>XL</given-names></name><etal></etal></person-group><article-title>SARS-CoV nucleocapsid protein antagonizes IFN-beta response by targeting initial step of IFN-beta induction pathway, and its C-terminal region is critical for the antagonism</article-title><source>Virus Genes</source><year>2011</year><volume>42</volume><issue>1</issue><fpage>37</fpage><lpage>45</lpage><pub-id pub-id-type="doi">10.1007/s11262-010-0544-x</pub-id><pub-id pub-id-type="pmid">20976535</pub-id></element-citation></ref><ref id="CR95"><label>95.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Siu</surname><given-names>KL</given-names></name><etal></etal></person-group><article-title>Suppression of innate antiviral response by severe acute respiratory syndrome coronavirus M protein is mediated through the first transmembrane domain</article-title><source>Cell Mol Immunol</source><year>2014</year><volume>11</volume><issue>2</issue><fpage>141</fpage><lpage>149</lpage><pub-id pub-id-type="doi">10.1038/cmi.2013.61</pub-id><pub-id pub-id-type="pmid">24509444</pub-id></element-citation></ref><ref id="CR96"><label>96.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lui</surname><given-names>PY</given-names></name><etal></etal></person-group><article-title>Middle East respiratory syndrome coronavirus M protein suppresses type I interferon expression through the inhibition of TBK1-dependent phosphorylation of IRF3</article-title><source>Emerg Microbes Infect</source><year>2016</year><volume>5</volume><fpage>e39</fpage><pub-id pub-id-type="doi">10.1038/emi.2016.33</pub-id><pub-id pub-id-type="pmid">27094905</pub-id></element-citation></ref><ref id="CR97"><label>97.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yang</surname><given-names>Y</given-names></name><etal></etal></person-group><article-title>The structural and accessory proteins M, ORF 4a, ORF 4b, and ORF 5 of Middle East respiratory syndrome coronavirus (MERS-CoV) are potent interferon antagonists</article-title><source>Protein Cell</source><year>2013</year><volume>4</volume><issue>12</issue><fpage>951</fpage><lpage>961</lpage><pub-id pub-id-type="doi">10.1007/s13238-013-3096-8</pub-id><pub-id pub-id-type="pmid">24318862</pub-id></element-citation></ref><ref id="CR98"><label>98.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chu</surname><given-names>CM</given-names></name><etal></etal></person-group><article-title>Initial viral load and the outcomes of SARS</article-title><source>CMAJ</source><year>2004</year><volume>171</volume><issue>11</issue><fpage>1349</fpage><lpage>1352</lpage><pub-id pub-id-type="doi">10.1503/cmaj.1040398</pub-id><pub-id pub-id-type="pmid">15557587</pub-id></element-citation></ref><ref id="CR99"><label>99.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ng</surname><given-names>ML</given-names></name><etal></etal></person-group><article-title>Proliferative growth of SARS coronavirus in Vero E6 cells</article-title><source>J Gen Virol</source><year>2003</year><volume>84</volume><issue>Pt 12</issue><fpage>3291</fpage><lpage>3303</lpage><pub-id pub-id-type="doi">10.1099/vir.0.19505-0</pub-id><pub-id pub-id-type="pmid">14645910</pub-id></element-citation></ref><ref id="CR100"><label>100.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Oh</surname><given-names>MD</given-names></name><etal></etal></person-group><article-title>Viral load kinetics of MERS coronavirus infection</article-title><source>N Engl J Med</source><year>2016</year><volume>375</volume><issue>13</issue><fpage>1303</fpage><lpage>1305</lpage><pub-id pub-id-type="doi">10.1056/NEJMc1511695</pub-id><pub-id pub-id-type="pmid">27682053</pub-id></element-citation></ref><ref id="CR101"><label>101.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Herold</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>Lung epithelial apoptosis in influenza virus pneumonia: the role of macrophage-expressed TNF-related apoptosis-inducing ligand</article-title><source>J Exp Med</source><year>2008</year><volume>205</volume><issue>13</issue><fpage>3065</fpage><lpage>3077</lpage><pub-id pub-id-type="doi">10.1084/jem.20080201</pub-id><pub-id pub-id-type="pmid">19064696</pub-id></element-citation></ref><ref id="CR102"><label>102.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hogner</surname><given-names>K</given-names></name><etal></etal></person-group><article-title>Macrophage-expressed IFN-beta contributes to apoptotic alveolar epithelial cell injury in severe influenza virus pneumonia</article-title><source>PLoS Pathog</source><year>2013</year><volume>9</volume><issue>2</issue><fpage>e1003188</fpage><pub-id pub-id-type="doi">10.1371/journal.ppat.1003188</pub-id><pub-id pub-id-type="pmid">23468627</pub-id></element-citation></ref><ref id="CR103"><label>103.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rodrigue-Gervais</surname><given-names>IG</given-names></name><etal></etal></person-group><article-title>Cellular inhibitor of apoptosis protein cIAP2 protects against pulmonary tissue necrosis during influenza virus infection to promote host survival</article-title><source>Cell Host Microbe</source><year>2014</year><volume>15</volume><issue>1</issue><fpage>23</fpage><lpage>35</lpage><pub-id pub-id-type="doi">10.1016/j.chom.2013.12.003</pub-id><pub-id pub-id-type="pmid">24439895</pub-id></element-citation></ref><ref id="CR104"><label>104.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zhao</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>T cell responses are required for protection from clinical disease and for virus clearance in severe acute respiratory syndrome coronavirus-infected mice</article-title><source>J Virol</source><year>2010</year><volume>84</volume><issue>18</issue><fpage>9318</fpage><lpage>9325</lpage><pub-id pub-id-type="doi">10.1128/JVI.01049-10</pub-id><pub-id pub-id-type="pmid">20610717</pub-id></element-citation></ref><ref id="CR105"><label>105.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kim</surname><given-names>KD</given-names></name><etal></etal></person-group><article-title>Adaptive immune cells temper initial innate responses</article-title><source>Nat Med</source><year>2007</year><volume>13</volume><issue>10</issue><fpage>1248</fpage><lpage>1252</lpage><pub-id pub-id-type="doi">10.1038/nm1633</pub-id><pub-id pub-id-type="pmid">17891146</pub-id></element-citation></ref><ref id="CR106"><label>106.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Palm</surname><given-names>NW</given-names></name><name><surname>Medzhitov</surname><given-names>R</given-names></name></person-group><article-title>Not so fast: adaptive suppression of innate immunity</article-title><source>Nat Med</source><year>2007</year><volume>13</volume><issue>10</issue><fpage>1142</fpage><lpage>1144</lpage><pub-id pub-id-type="doi">10.1038/nm1007-1142b</pub-id><pub-id pub-id-type="pmid">17917657</pub-id></element-citation></ref><ref id="CR107"><label>107.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zornetzer</surname><given-names>GA</given-names></name><etal></etal></person-group><article-title>Transcriptomic analysis reveals a mechanism for a prefibrotic phenotype in STAT1 knockout mice during severe acute respiratory syndrome coronavirus infection</article-title><source>J Virol</source><year>2010</year><volume>84</volume><issue>21</issue><fpage>11297</fpage><lpage>11309</lpage><pub-id pub-id-type="doi">10.1128/JVI.01130-10</pub-id><pub-id pub-id-type="pmid">20702617</pub-id></element-citation></ref><ref id="CR108"><label>108.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Page</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>Induction of alternatively activated macrophages enhances pathogenesis during severe acute respiratory syndrome coronavirus infection</article-title><source>J Virol</source><year>2012</year><volume>86</volume><issue>24</issue><fpage>13334</fpage><lpage>13349</lpage><pub-id pub-id-type="doi">10.1128/JVI.01689-12</pub-id><pub-id pub-id-type="pmid">23015710</pub-id></element-citation></ref><ref id="CR109"><label>109.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gralinski</surname><given-names>LE</given-names></name><etal></etal></person-group><article-title>Genome wide identification of SARS-CoV susceptibility loci using the collaborative cross</article-title><source>PLoS Genet</source><year>2015</year><volume>11</volume><issue>10</issue><fpage>e1005504</fpage><pub-id pub-id-type="doi">10.1371/journal.pgen.1005504</pub-id><pub-id pub-id-type="pmid">26452100</pub-id></element-citation></ref><ref id="CR110"><label>110.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Drosten</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>Clinical features and virological analysis of a case of Middle East respiratory syndrome coronavirus infection</article-title><source>Lancet Infect Dis</source><year>2013</year><volume>13</volume><issue>9</issue><fpage>745</fpage><lpage>751</lpage><pub-id pub-id-type="doi">10.1016/S1473-3099(13)70154-3</pub-id><pub-id pub-id-type="pmid">23782859</pub-id></element-citation></ref><ref id="CR111"><label>111.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lew</surname><given-names>TW</given-names></name><etal></etal></person-group><article-title>Acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome</article-title><source>JAMA</source><year>2003</year><volume>290</volume><issue>3</issue><fpage>374</fpage><lpage>380</lpage><pub-id pub-id-type="doi">10.1001/jama.290.3.374</pub-id><pub-id pub-id-type="pmid">12865379</pub-id></element-citation></ref><ref id="CR112"><label>112.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jiang</surname><given-names>Y</given-names></name><etal></etal></person-group><article-title>Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome</article-title><source>Am J Respir Crit Care Med</source><year>2005</year><volume>171</volume><issue>8</issue><fpage>850</fpage><lpage>857</lpage><pub-id pub-id-type="doi">10.1164/rccm.200407-857OC</pub-id><pub-id pub-id-type="pmid">15657466</pub-id></element-citation></ref><ref id="CR113"><label>113.</label><mixed-citation publication-type="other">Reghunathan R et al (2005) Expression profile of immune response genes in patients with Severe Acute Respiratory Syndrome. BMC Immunology 6:2</mixed-citation></ref><ref id="CR114"><label>114.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Stockman</surname><given-names>LJ</given-names></name><etal></etal></person-group><article-title>SARS: systematic review of treatment effects</article-title><source>PLoS Med</source><year>2006</year><volume>3</volume><issue>9</issue><fpage>e343</fpage><pub-id pub-id-type="doi">10.1371/journal.pmed.0030343</pub-id><pub-id pub-id-type="pmid">16968120</pub-id></element-citation></ref><ref id="CR115"><label>115.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Al-Tawfiq</surname><given-names>JA</given-names></name><etal></etal></person-group><article-title>Ribavirin and interferon therapy in patients infected with the Middle East respiratory syndrome coronavirus: an observational study</article-title><source>Int J Infect Dis</source><year>2014</year><volume>20</volume><fpage>42</fpage><lpage>46</lpage><pub-id pub-id-type="doi">10.1016/j.ijid.2013.12.003</pub-id><pub-id pub-id-type="pmid">24406736</pub-id></element-citation></ref><ref id="CR116"><label>116.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Falzarano</surname><given-names>D</given-names></name><etal></etal></person-group><article-title>Treatment with interferon-alpha2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques</article-title><source>Nat Med</source><year>2013</year><volume>19</volume><issue>10</issue><fpage>1313</fpage><lpage>1317</lpage><pub-id pub-id-type="doi">10.1038/nm.3362</pub-id><pub-id pub-id-type="pmid">24013700</pub-id></element-citation></ref><ref id="CR117"><label>117.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Omrani</surname><given-names>AS</given-names></name><etal></etal></person-group><article-title>Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: a retrospective cohort study</article-title><source>Lancet Infect Dis</source><year>2014</year><volume>14</volume><issue>11</issue><fpage>1090</fpage><lpage>1095</lpage><pub-id pub-id-type="doi">10.1016/S1473-3099(14)70920-X</pub-id><pub-id pub-id-type="pmid">25278221</pub-id></element-citation></ref><ref id="CR118"><label>118.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Auyeung</surname><given-names>TW</given-names></name><etal></etal></person-group><article-title>The use of corticosteroid as treatment in SARS was associated with adverse outcomes: a retrospective cohort study</article-title><source>J Infect</source><year>2005</year><volume>51</volume><issue>2</issue><fpage>98</fpage><lpage>102</lpage><pub-id pub-id-type="doi">10.1016/j.jinf.2004.09.008</pub-id><pub-id pub-id-type="pmid">16038758</pub-id></element-citation></ref><ref id="CR119"><label>119.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ho</surname><given-names>JC</given-names></name><etal></etal></person-group><article-title>High-dose pulse versus nonpulse corticosteroid regimens in severe acute respiratory syndrome</article-title><source>Am J Respir Crit Care Med</source><year>2003</year><volume>168</volume><issue>12</issue><fpage>1449</fpage><lpage>1456</lpage><pub-id pub-id-type="doi">10.1164/rccm.200306-766OC</pub-id><pub-id pub-id-type="pmid">12947028</pub-id></element-citation></ref><ref id="CR120"><label>120.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yam</surname><given-names>LY</given-names></name><etal></etal></person-group><article-title>Corticosteroid treatment of severe acute respiratory syndrome in Hong Kong</article-title><source>J Infect</source><year>2007</year><volume>54</volume><issue>1</issue><fpage>28</fpage><lpage>39</lpage><pub-id pub-id-type="doi">10.1016/j.jinf.2006.01.005</pub-id><pub-id pub-id-type="pmid">16542729</pub-id></element-citation></ref><ref id="CR121"><label>121.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Haagmans</surname><given-names>BL</given-names></name><etal></etal></person-group><article-title>Pegylated interferon-alpha protects type 1 pneumocytes against SARS coronavirus infection in macaques</article-title><source>Nat Med</source><year>2004</year><volume>10</volume><issue>3</issue><fpage>290</fpage><lpage>293</lpage><pub-id pub-id-type="doi">10.1038/nm1001</pub-id><pub-id pub-id-type="pmid">14981511</pub-id></element-citation></ref><ref id="CR122"><label>122.</label><mixed-citation publication-type="other">Zumla A et al (2016) Coronaviruses—drug discovery and therapeutic options. Nat Rev Drug Discov 15(5):327–47</mixed-citation></ref><ref id="CR123"><label>123.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Davidson</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>IFNlambda is a potent anti-influenza therapeutic without the inflammatory side effects of IFNalpha treatment</article-title><source>EMBO Mol Med</source><year>2016</year><volume>8</volume><issue>9</issue><fpage>1099</fpage><lpage>1112</lpage><pub-id pub-id-type="doi">10.15252/emmm.201606413</pub-id><pub-id pub-id-type="pmid">27520969</pub-id></element-citation></ref><ref id="CR124"><label>124.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Blazek</surname><given-names>K</given-names></name><etal></etal></person-group><article-title>IFN-lambda resolves inflammation via suppression of neutrophil infiltration and IL-1beta production</article-title><source>J Exp Med</source><year>2015</year><volume>212</volume><issue>6</issue><fpage>845</fpage><lpage>853</lpage><pub-id pub-id-type="doi">10.1084/jem.20140995</pub-id><pub-id pub-id-type="pmid">25941255</pub-id></element-citation></ref><ref id="CR125"><label>125.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Imai</surname><given-names>Y</given-names></name><etal></etal></person-group><article-title>Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury</article-title><source>Cell</source><year>2008</year><volume>133</volume><issue>2</issue><fpage>235</fpage><lpage>249</lpage><pub-id pub-id-type="doi">10.1016/j.cell.2008.02.043</pub-id><pub-id pub-id-type="pmid">18423196</pub-id></element-citation></ref><ref id="CR126"><label>126.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Shirey</surname><given-names>KA</given-names></name><etal></etal></person-group><article-title>The TLR4 antagonist Eritoran protects mice from lethal influenza infection</article-title><source>Nature</source><year>2013</year><volume>497</volume><issue>7450</issue><fpage>498</fpage><lpage>502</lpage><pub-id pub-id-type="doi">10.1038/nature12118</pub-id><pub-id pub-id-type="pmid">23636320</pub-id></element-citation></ref><ref id="CR127"><label>127.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Teijaro</surname><given-names>JR</given-names></name><etal></etal></person-group><article-title>Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection</article-title><source>Cell</source><year>2011</year><volume>146</volume><issue>6</issue><fpage>980</fpage><lpage>991</lpage><pub-id pub-id-type="doi">10.1016/j.cell.2011.08.015</pub-id><pub-id pub-id-type="pmid">21925319</pub-id></element-citation></ref><ref id="CR128"><label>128.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Walsh</surname><given-names>KB</given-names></name><etal></etal></person-group><article-title>Suppression of cytokine storm with a sphingosine analog provides protection against pathogenic influenza virus</article-title><source>Proc Natl Acad Sci U S A</source><year>2011</year><volume>108</volume><issue>29</issue><fpage>12018</fpage><lpage>12023</lpage><pub-id pub-id-type="doi">10.1073/pnas.1107024108</pub-id><pub-id pub-id-type="pmid">21715659</pub-id></element-citation></ref><ref id="CR129"><label>129.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Leuschner</surname><given-names>F</given-names></name><etal></etal></person-group><article-title>Silencing of CCR2 in myocarditis</article-title><source>Eur Heart J</source><year>2015</year><volume>36</volume><issue>23</issue><fpage>1478</fpage><lpage>1488</lpage><pub-id pub-id-type="doi">10.1093/eurheartj/ehu225</pub-id><pub-id pub-id-type="pmid">24950695</pub-id></element-citation></ref><ref id="CR130"><label>130.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Leuschner</surname><given-names>F</given-names></name><etal></etal></person-group><article-title>Therapeutic siRNA silencing in inflammatory monocytes in mice</article-title><source>Nat Biotechnol</source><year>2011</year><volume>29</volume><issue>11</issue><fpage>1005</fpage><lpage>1010</lpage><pub-id pub-id-type="doi">10.1038/nbt.1989</pub-id><pub-id pub-id-type="pmid">21983520</pub-id></element-citation></ref><ref id="CR131"><label>131.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Darwish</surname><given-names>I</given-names></name><etal></etal></person-group><article-title>Immunomodulatory therapy for severe influenza</article-title><source>Expert Rev Anti-Infect Ther</source><year>2011</year><volume>9</volume><issue>7</issue><fpage>807</fpage><lpage>822</lpage><pub-id pub-id-type="doi">10.1586/eri.11.56</pub-id><pub-id pub-id-type="pmid">21810053</pub-id></element-citation></ref><ref id="CR132"><label>132.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>McDermott</surname><given-names>JE</given-names></name><etal></etal></person-group><article-title>The effect of inhibition of PP1 and TNFalpha signaling on pathogenesis of SARS coronavirus</article-title><source>BMC Syst Biol</source><year>2016</year><volume>10</volume><issue>1</issue><fpage>93</fpage><pub-id pub-id-type="doi">10.1186/s12918-016-0336-6</pub-id><pub-id 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