Lethal Synergism between Influenza and Streptococcus pneumoniae
Identifieur interne : 000C67 ( Pmc/Corpus ); précédent : 000C66; suivant : 000C68Lethal Synergism between Influenza and Streptococcus pneumoniae
Auteurs : Jennifer M. Rudd ; Harshini K. Ashar ; Vincent Tk Chow ; Narasaraju TeluguakulaSource :
- Journal of infectious pulmonary diseases [ 2470-3176 ] ; 2016.
Abstract
The devastating synergism of bacterial pneumonia with influenza viral infections left its mark on the world over the last century. Although the details of pathogenesis remain unclear, the synergism is related to a variety of factors including pulmonary epithelial barrier damage which exposes receptors that influence bacterial adherence and the triggering of an exaggerated innate immune response and cytokine storm, which further acts to worsen the injury. Several therapeutics and combination therapies of antibiotics, anti-inflammatories including corticosteroids and toll-like receptor modifiers, and anti-virals are being discussed. This mini review summarizes recent developments in unearthing the pathogenesis of the lethal synergism of pneumococcal co-infection following influenza, as well as addresses potential therapeutic options and combinations of therapies currently being evaluated.
Url:
PubMed: 27981251
PubMed Central: 5154682
Links to Exploration step
PMC:5154682Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Lethal Synergism between Influenza and <italic>Streptococcus pneumoniae</italic></title><author><name sortKey="Rudd, Jennifer M" sort="Rudd, Jennifer M" uniqKey="Rudd J" first="Jennifer M" last="Rudd">Jennifer M. Rudd</name><affiliation><nlm:aff id="A1">Center for Veterinary Health Sciences, Oklahoma State University, OK, USA</nlm:aff></affiliation></author><author><name sortKey="Ashar, Harshini K" sort="Ashar, Harshini K" uniqKey="Ashar H" first="Harshini K" last="Ashar">Harshini K. Ashar</name><affiliation><nlm:aff id="A1">Center for Veterinary Health Sciences, Oklahoma State University, OK, USA</nlm:aff></affiliation></author><author><name sortKey="Chow, Vincent Tk" sort="Chow, Vincent Tk" uniqKey="Chow V" first="Vincent Tk" last="Chow">Vincent Tk Chow</name><affiliation><nlm:aff id="A2">Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore</nlm:aff></affiliation></author><author><name sortKey="Teluguakula, Narasaraju" sort="Teluguakula, Narasaraju" uniqKey="Teluguakula N" first="Narasaraju" last="Teluguakula">Narasaraju Teluguakula</name><affiliation><nlm:aff id="A1">Center for Veterinary Health Sciences, Oklahoma State University, OK, USA</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27981251</idno><idno type="pmc">5154682</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154682</idno><idno type="RBID">PMC:5154682</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000C67</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000C67</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Lethal Synergism between Influenza and <italic>Streptococcus pneumoniae</italic></title><author><name sortKey="Rudd, Jennifer M" sort="Rudd, Jennifer M" uniqKey="Rudd J" first="Jennifer M" last="Rudd">Jennifer M. Rudd</name><affiliation><nlm:aff id="A1">Center for Veterinary Health Sciences, Oklahoma State University, OK, USA</nlm:aff></affiliation></author><author><name sortKey="Ashar, Harshini K" sort="Ashar, Harshini K" uniqKey="Ashar H" first="Harshini K" last="Ashar">Harshini K. Ashar</name><affiliation><nlm:aff id="A1">Center for Veterinary Health Sciences, Oklahoma State University, OK, USA</nlm:aff></affiliation></author><author><name sortKey="Chow, Vincent Tk" sort="Chow, Vincent Tk" uniqKey="Chow V" first="Vincent Tk" last="Chow">Vincent Tk Chow</name><affiliation><nlm:aff id="A2">Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore</nlm:aff></affiliation></author><author><name sortKey="Teluguakula, Narasaraju" sort="Teluguakula, Narasaraju" uniqKey="Teluguakula N" first="Narasaraju" last="Teluguakula">Narasaraju Teluguakula</name><affiliation><nlm:aff id="A1">Center for Veterinary Health Sciences, Oklahoma State University, OK, USA</nlm:aff></affiliation></author></analytic><series><title level="j">Journal of infectious pulmonary diseases</title><idno type="eISSN">2470-3176</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">The devastating synergism of bacterial pneumonia with influenza viral infections left its mark on the world over the last century. Although the details of pathogenesis remain unclear, the synergism is related to a variety of factors including pulmonary epithelial barrier damage which exposes receptors that influence bacterial adherence and the triggering of an exaggerated innate immune response and cytokine storm, which further acts to worsen the injury. Several therapeutics and combination therapies of antibiotics, anti-inflammatories including corticosteroids and toll-like receptor modifiers, and anti-virals are being discussed. This mini review summarizes recent developments in unearthing the pathogenesis of the lethal synergism of pneumococcal co-infection following influenza, as well as addresses potential therapeutic options and combinations of therapies currently being evaluated.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Mccullers, Ja" uniqKey="Mccullers J">JA McCullers</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chertow, Ds" uniqKey="Chertow D">DS Chertow</name></author><author><name sortKey="Memoli, Mj" uniqKey="Memoli M">MJ Memoli</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kash, Jc" uniqKey="Kash J">JC Kash</name></author><author><name sortKey="Taubenberger, Jk" uniqKey="Taubenberger J">JK Taubenberger</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Madhi, Sa" uniqKey="Madhi S">SA Madhi</name></author><author><name sortKey="Schoub, B" uniqKey="Schoub B">B Schoub</name></author><author><name sortKey="Klugman, Kp" uniqKey="Klugman K">KP Klugman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rynda Apple, A" uniqKey="Rynda Apple A">A Rynda-Apple</name></author><author><name sortKey="Robinson, Km" uniqKey="Robinson K">KM Robinson</name></author><author><name sortKey="Alcorn, Jf" uniqKey="Alcorn J">JF Alcorn</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Morens, Dm" uniqKey="Morens D">DM Morens</name></author><author><name sortKey="Taubenberger, Jk" uniqKey="Taubenberger J">JK Taubenberger</name></author><author><name sortKey="Fauci, As" uniqKey="Fauci A">AS Fauci</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Viboud, C" uniqKey="Viboud C">C Viboud</name></author><author><name sortKey="Simonsen, L" uniqKey="Simonsen L">L Simonsen</name></author><author><name sortKey="Fuentes, R" uniqKey="Fuentes R">R Fuentes</name></author><author><name sortKey="Flores, J" uniqKey="Flores J">J Flores</name></author><author><name sortKey="Miller, Ma" uniqKey="Miller M">MA Miller</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Viboud, C" uniqKey="Viboud C">C Viboud</name></author><author><name sortKey="Grais, Rf" uniqKey="Grais R">RF Grais</name></author><author><name sortKey="Lafont, Ba" uniqKey="Lafont B">BA Lafont</name></author><author><name sortKey="Miller, Ma" uniqKey="Miller M">MA Miller</name></author><author><name sortKey="Simonsen, L" uniqKey="Simonsen L">L Simonsen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ortiz, Jr" uniqKey="Ortiz J">JR Ortiz</name></author><author><name sortKey="Lafond, Ke" uniqKey="Lafond K">KE Lafond</name></author><author><name sortKey="Wong, Ta" uniqKey="Wong T">TA Wong</name></author><author><name sortKey="Uyeki, Tm" uniqKey="Uyeki T">TM Uyeki</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mccullers, Ja" uniqKey="Mccullers J">JA McCullers</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gupta, Rk" uniqKey="Gupta R">RK Gupta</name></author><author><name sortKey="George, R" uniqKey="George R">R George</name></author><author><name sortKey="Nguyen Van Tam, Js" uniqKey="Nguyen Van Tam J">JS Nguyen-Van-Tam</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wang, Xy" uniqKey="Wang X">XY Wang</name></author><author><name sortKey="Kilgore, Pe" uniqKey="Kilgore P">PE Kilgore</name></author><author><name sortKey="Lim, Ka" uniqKey="Lim K">KA Lim</name></author><author><name sortKey="Wang, Sm" uniqKey="Wang S">SM Wang</name></author><author><name sortKey="Lee, J" uniqKey="Lee J">J Lee</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Herzog, H" uniqKey="Herzog H">H Herzog</name></author><author><name sortKey="Staub, H" uniqKey="Staub H">H Staub</name></author><author><name sortKey="Richterich, R" uniqKey="Richterich R">R Richterich</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mccullers, Ja" uniqKey="Mccullers J">JA McCullers</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mccullers, Ja" uniqKey="Mccullers J">JA McCullers</name></author><author><name sortKey="Mcauley, Jl" uniqKey="Mcauley J">JL McAuley</name></author><author><name sortKey="Browall, S" uniqKey="Browall S">S Browall</name></author><author><name sortKey="Iverson, Ar" uniqKey="Iverson A">AR Iverson</name></author><author><name sortKey="Boyd, Kl" uniqKey="Boyd K">KL Boyd</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dockrell, Dh" uniqKey="Dockrell D">DH Dockrell</name></author><author><name sortKey="Whyte, Mk" uniqKey="Whyte M">MK Whyte</name></author><author><name sortKey="Mitchell, Tj" uniqKey="Mitchell T">TJ Mitchell</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Moorthy, An" uniqKey="Moorthy A">AN Moorthy</name></author><author><name sortKey="Rai, P" uniqKey="Rai P">P Rai</name></author><author><name sortKey="Jiao, H" uniqKey="Jiao H">H Jiao</name></author><author><name sortKey="Wang, S" uniqKey="Wang S">S Wang</name></author><author><name sortKey="Tan, Kb" uniqKey="Tan K">KB Tan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Levine, Am" uniqKey="Levine A">AM LeVine</name></author><author><name sortKey="Koeningsknecht, V" uniqKey="Koeningsknecht V">V Koeningsknecht</name></author><author><name sortKey="Stark, Jm" uniqKey="Stark J">JM Stark</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Loosli, Cg" uniqKey="Loosli C">CG Loosli</name></author><author><name sortKey="Stinson, Sf" uniqKey="Stinson S">SF Stinson</name></author><author><name sortKey="Ryan, Dp" uniqKey="Ryan D">DP Ryan</name></author><author><name sortKey="Hertweck, Ms" uniqKey="Hertweck M">MS Hertweck</name></author><author><name sortKey="Hardy, Jd" uniqKey="Hardy J">JD Hardy</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kash, Jc" uniqKey="Kash J">JC Kash</name></author><author><name sortKey="Walters, Ka" uniqKey="Walters K">KA Walters</name></author><author><name sortKey="Davis, As" uniqKey="Davis A">AS Davis</name></author><author><name sortKey="Sandouk, A" uniqKey="Sandouk A">A Sandouk</name></author><author><name sortKey="Schwartzman, Lm" uniqKey="Schwartzman L">LM Schwartzman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Florescu, Df" uniqKey="Florescu D">DF Florescu</name></author><author><name sortKey="Kalil, Ac" uniqKey="Kalil A">AC Kalil</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nita Lazar, M" uniqKey="Nita Lazar M">M Nita-Lazar</name></author><author><name sortKey="Banerjee, A" uniqKey="Banerjee A">A Banerjee</name></author><author><name sortKey="Feng, C" uniqKey="Feng C">C Feng</name></author><author><name sortKey="Amin, Mn" uniqKey="Amin M">MN Amin</name></author><author><name sortKey="Frieman, Mb" uniqKey="Frieman M">MB Frieman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mccullers, Ja" uniqKey="Mccullers J">JA McCullers</name></author><author><name sortKey="Rehg, Je" uniqKey="Rehg J">JE Rehg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Feldman, C" uniqKey="Feldman C">C Feldman</name></author><author><name sortKey="Anderson, R" uniqKey="Anderson R">R Anderson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mcnamee, La" uniqKey="Mcnamee L">LA McNamee</name></author><author><name sortKey="Harmsen, Ag" uniqKey="Harmsen A">AG Harmsen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Damjanovic, D" uniqKey="Damjanovic D">D Damjanovic</name></author><author><name sortKey="Lai, R" uniqKey="Lai R">R Lai</name></author><author><name sortKey="Jeyanathan, M" uniqKey="Jeyanathan M">M Jeyanathan</name></author><author><name sortKey="Hogaboam, Cm" uniqKey="Hogaboam C">CM Hogaboam</name></author><author><name sortKey="Xing, Z" uniqKey="Xing Z">Z Xing</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Okumura, Cy" uniqKey="Okumura C">CY Okumura</name></author><author><name sortKey="Nizet, V" uniqKey="Nizet V">V Nizet</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sun, K" uniqKey="Sun K">K Sun</name></author><author><name sortKey="Metzger, Dw" uniqKey="Metzger D">DW Metzger</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Robinson, Km" uniqKey="Robinson K">KM Robinson</name></author><author><name sortKey="Kolls, Jk" uniqKey="Kolls J">JK Kolls</name></author><author><name sortKey="Alcorn, Jf" uniqKey="Alcorn J">JF Alcorn</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Narasaraju, T" uniqKey="Narasaraju T">T Narasaraju</name></author><author><name sortKey="Yang, E" uniqKey="Yang E">E Yang</name></author><author><name sortKey="Samy, Rp" uniqKey="Samy R">RP Samy</name></author><author><name sortKey="Ng, Hh" uniqKey="Ng H">HH Ng</name></author><author><name sortKey="Poh, Wp" uniqKey="Poh W">WP Poh</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brinkmann, V" uniqKey="Brinkmann V">V Brinkmann</name></author><author><name sortKey="Reichard, U" uniqKey="Reichard U">U Reichard</name></author><author><name sortKey="Goosmann, C" uniqKey="Goosmann C">C Goosmann</name></author><author><name sortKey="Fauler, B" uniqKey="Fauler B">B Fauler</name></author><author><name sortKey="Uhlemann, Y" uniqKey="Uhlemann Y">Y Uhlemann</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Saffarzadeh, M" uniqKey="Saffarzadeh M">M Saffarzadeh</name></author><author><name sortKey="Juenemann, C" uniqKey="Juenemann C">C Juenemann</name></author><author><name sortKey="Queisser, Ma" uniqKey="Queisser M">MA Queisser</name></author><author><name sortKey="Lochnit, G" uniqKey="Lochnit G">G Lochnit</name></author><author><name sortKey="Barreto, G" uniqKey="Barreto G">G Barreto</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Narayana Moorthy, A" uniqKey="Narayana Moorthy A">A Narayana Moorthy</name></author><author><name sortKey="Narasaraju, T" uniqKey="Narasaraju T">T Narasaraju</name></author><author><name sortKey="Rai, P" uniqKey="Rai P">P Rai</name></author><author><name sortKey="Perumalsamy, R" uniqKey="Perumalsamy R">R Perumalsamy</name></author><author><name sortKey="Tan, Kb" uniqKey="Tan K">KB Tan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Abrams, St" uniqKey="Abrams S">ST Abrams</name></author><author><name sortKey="Zhang, N" uniqKey="Zhang N">N Zhang</name></author><author><name sortKey="Manson, J" uniqKey="Manson J">J Manson</name></author><author><name sortKey="Liu, T" uniqKey="Liu T">T Liu</name></author><author><name sortKey="Dart, C" uniqKey="Dart C">C Dart</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Short, Kr" uniqKey="Short K">KR Short</name></author><author><name sortKey="Von Kockritz Blickwede, M" uniqKey="Von Kockritz Blickwede M">M von Köckritz-Blickwede</name></author><author><name sortKey="Langereis, Jd" uniqKey="Langereis J">JD Langereis</name></author><author><name sortKey="Chew, Ky" uniqKey="Chew K">KY Chew</name></author><author><name sortKey="Job, Er" uniqKey="Job E">ER Job</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Czaikoski, Pg" uniqKey="Czaikoski P">PG Czaikoski</name></author><author><name sortKey="Mota, Jm" uniqKey="Mota J">JM Mota</name></author><author><name sortKey="Nascimento, Dc" uniqKey="Nascimento D">DC Nascimento</name></author><author><name sortKey="Sonego, F" uniqKey="Sonego F">F Sônego</name></author><author><name sortKey="Castanheira, Fv" uniqKey="Castanheira F">FV Castanheira</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mori, Y" uniqKey="Mori Y">Y Mori</name></author><author><name sortKey="Yamaguchi, M" uniqKey="Yamaguchi M">M Yamaguchi</name></author><author><name sortKey="Terao, Y" uniqKey="Terao Y">Y Terao</name></author><author><name sortKey="Hamada, S" uniqKey="Hamada S">S Hamada</name></author><author><name sortKey="Ooshima, T" uniqKey="Ooshima T">T Ooshima</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhu, L" uniqKey="Zhu L">L Zhu</name></author><author><name sortKey="Kuang, Z" uniqKey="Kuang Z">Z Kuang</name></author><author><name sortKey="Wilson, Ba" uniqKey="Wilson B">BA Wilson</name></author><author><name sortKey="Lau, Gw" uniqKey="Lau G">GW Lau</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ellis, Gt" uniqKey="Ellis G">GT Ellis</name></author><author><name sortKey="Davidson, S" uniqKey="Davidson S">S Davidson</name></author><author><name sortKey="Crotta, S" uniqKey="Crotta S">S Crotta</name></author><author><name sortKey="Branzk, N" uniqKey="Branzk N">N Branzk</name></author><author><name sortKey="Papayannopoulos, V" uniqKey="Papayannopoulos V">V Papayannopoulos</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Engelich, G" uniqKey="Engelich G">G Engelich</name></author><author><name sortKey="White, M" uniqKey="White M">M White</name></author><author><name sortKey="Hartshorn, Kl" uniqKey="Hartshorn K">KL Hartshorn</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Richard, Al" uniqKey="Richard A">AL Richard</name></author><author><name sortKey="Siegel, Sj" uniqKey="Siegel S">SJ Siegel</name></author><author><name sortKey="Erikson, J" uniqKey="Erikson J">J Erikson</name></author><author><name sortKey="Weiser, Jn" uniqKey="Weiser J">JN Weiser</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yoshimura, A" uniqKey="Yoshimura A">A Yoshimura</name></author><author><name sortKey="Lien, E" uniqKey="Lien E">E Lien</name></author><author><name sortKey="Ingalls, Rr" uniqKey="Ingalls R">RR Ingalls</name></author><author><name sortKey="Tuomanen, E" uniqKey="Tuomanen E">E Tuomanen</name></author><author><name sortKey="Dziarski, R" uniqKey="Dziarski R">R Dziarski</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Spelmink, L" uniqKey="Spelmink L">L Spelmink</name></author><author><name sortKey="Sender, V" uniqKey="Sender V">V Sender</name></author><author><name sortKey="Hentrich, K" uniqKey="Hentrich K">K Hentrich</name></author><author><name sortKey="Kuri, T" uniqKey="Kuri T">T Kuri</name></author><author><name sortKey="Plant, L" uniqKey="Plant L">L Plant</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tian, X" uniqKey="Tian X">X Tian</name></author><author><name sortKey="Xu, F" uniqKey="Xu F">F Xu</name></author><author><name sortKey="Lung, Wy" uniqKey="Lung W">WY Lung</name></author><author><name sortKey="Meyerson, C" uniqKey="Meyerson C">C Meyerson</name></author><author><name sortKey="Ghaffari, Aa" uniqKey="Ghaffari A">AA Ghaffari</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Li, W" uniqKey="Li W">W Li</name></author><author><name sortKey="Moltedo, B" uniqKey="Moltedo B">B Moltedo</name></author><author><name sortKey="Moran, Tm" uniqKey="Moran T">TM Moran</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shahangian, A" uniqKey="Shahangian A">A Shahangian</name></author><author><name sortKey="Chow, Ek" uniqKey="Chow E">EK Chow</name></author><author><name sortKey="Tian, X" uniqKey="Tian X">X Tian</name></author><author><name sortKey="Kang, Jr" uniqKey="Kang J">JR Kang</name></author><author><name sortKey="Ghaffari, A" uniqKey="Ghaffari A">A Ghaffari</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="O Rien, Rl" uniqKey="O Rien R">RL O’Brien</name></author><author><name sortKey="Roark, Cl" uniqKey="Roark C">CL Roark</name></author><author><name sortKey="Jin, N" uniqKey="Jin N">N Jin</name></author><author><name sortKey="Aydintug, Mk" uniqKey="Aydintug M">MK Aydintug</name></author><author><name sortKey="French, Jd" uniqKey="French J">JD French</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Negishi, H" uniqKey="Negishi H">H Negishi</name></author><author><name sortKey="Yanai, H" uniqKey="Yanai H">H Yanai</name></author><author><name sortKey="Nakajima, A" uniqKey="Nakajima A">A Nakajima</name></author><author><name sortKey="Koshiba, R" uniqKey="Koshiba R">R Koshiba</name></author><author><name sortKey="Atarashi, K" uniqKey="Atarashi K">K Atarashi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Malley, R" uniqKey="Malley R">R Malley</name></author><author><name sortKey="Henneke, P" uniqKey="Henneke P">P Henneke</name></author><author><name sortKey="Morse, Sc" uniqKey="Morse S">SC Morse</name></author><author><name sortKey="Cieslewicz, Mj" uniqKey="Cieslewicz M">MJ Cieslewicz</name></author><author><name sortKey="Lipsitch, M" uniqKey="Lipsitch M">M Lipsitch</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Karlstrom, A" uniqKey="Karlstrom A">A Karlström</name></author><author><name sortKey="Heston, Sm" uniqKey="Heston S">SM Heston</name></author><author><name sortKey="Boyd, Kl" uniqKey="Boyd K">KL Boyd</name></author><author><name sortKey="Tuomanen, Ei" uniqKey="Tuomanen E">EI Tuomanen</name></author><author><name sortKey="Mccullers, Ja" uniqKey="Mccullers J">JA McCullers</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Waterer, Gw" uniqKey="Waterer G">GW Waterer</name></author><author><name sortKey="Somes, Gw" uniqKey="Somes G">GW Somes</name></author><author><name sortKey="Wunderink, Rg" uniqKey="Wunderink R">RG Wunderink</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Watkins, Rr" uniqKey="Watkins R">RR Watkins</name></author><author><name sortKey="Lemonovich, Tl" uniqKey="Lemonovich T">TL Lemonovich</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Majhi, A" uniqKey="Majhi A">A Majhi</name></author><author><name sortKey="Adhikary, R" uniqKey="Adhikary R">R Adhikary</name></author><author><name sortKey="Bhattacharyya, A" uniqKey="Bhattacharyya A">A Bhattacharyya</name></author><author><name sortKey="Mahanti, S" uniqKey="Mahanti S">S Mahanti</name></author><author><name sortKey="Bishayi, B" uniqKey="Bishayi B">B Bishayi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Karlstrom, A" uniqKey="Karlstrom A">A Karlström</name></author><author><name sortKey="Boyd, Kl" uniqKey="Boyd K">KL Boyd</name></author><author><name sortKey="English, Bk" uniqKey="English B">BK English</name></author><author><name sortKey="Mccullers, Ja" uniqKey="Mccullers J">JA McCullers</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Majhi, A" uniqKey="Majhi A">A Majhi</name></author><author><name sortKey="Kundu, K" uniqKey="Kundu K">K Kundu</name></author><author><name sortKey="Adhikary, R" uniqKey="Adhikary R">R Adhikary</name></author><author><name sortKey="Banerjee, M" uniqKey="Banerjee M">M Banerjee</name></author><author><name sortKey="Mahanti, S" uniqKey="Mahanti S">S Mahanti</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Luxameechanporn, T" uniqKey="Luxameechanporn T">T Luxameechanporn</name></author><author><name sortKey="Blair, C" uniqKey="Blair C">C Blair</name></author><author><name sortKey="Kirtsreesakul, V" uniqKey="Kirtsreesakul V">V Kirtsreesakul</name></author><author><name sortKey="Thompson, K" uniqKey="Thompson K">K Thompson</name></author><author><name sortKey="Naclerio, Rm" uniqKey="Naclerio R">RM Naclerio</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Goldstein, Lh" uniqKey="Goldstein L">LH Goldstein</name></author><author><name sortKey="Gabin, A" uniqKey="Gabin A">A Gabin</name></author><author><name sortKey="Fawaz, A" uniqKey="Fawaz A">A Fawaz</name></author><author><name sortKey="Freedberg, Na" uniqKey="Freedberg N">NA Freedberg</name></author><author><name sortKey="Schwartz, N" uniqKey="Schwartz N">N Schwartz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Li, C" uniqKey="Li C">C Li</name></author><author><name sortKey="Yang, P" uniqKey="Yang P">P Yang</name></author><author><name sortKey="Zhang, Y" uniqKey="Zhang Y">Y Zhang</name></author><author><name sortKey="Sun, Y" uniqKey="Sun Y">Y Sun</name></author><author><name sortKey="Wang, W" uniqKey="Wang W">W Wang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ke, Han" uniqKey="Ke H">Han Ke</name></author><author><name sortKey="Ma, Huilai" uniqKey="Ma H">Huilai Ma</name></author><author><name sortKey="An, Xiangdong" uniqKey="An X">Xiangdong An</name></author><author><name sortKey="Su, Yang" uniqKey="Su Y">Yang Su</name></author><author><name sortKey="Chen, Jing" uniqKey="Chen J">Jing Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mifsud, Ej" uniqKey="Mifsud E">EJ Mifsud</name></author><author><name sortKey="Tan, Ac" uniqKey="Tan A">AC Tan</name></author><author><name sortKey="Short, Kr" uniqKey="Short K">KR Short</name></author><author><name sortKey="Brown, Le" uniqKey="Brown L">LE Brown</name></author><author><name sortKey="Chua, By" uniqKey="Chua B">BY Chua</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Reppe, K" uniqKey="Reppe K">K Reppe</name></author><author><name sortKey="Radunzel, P" uniqKey="Radunzel P">P Radünzel</name></author><author><name sortKey="Dietert, K" uniqKey="Dietert K">K Dietert</name></author><author><name sortKey="Tschernig, T" uniqKey="Tschernig T">T Tschernig</name></author><author><name sortKey="Wolff, T" uniqKey="Wolff T">T Wolff</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Porte, R" uniqKey="Porte R">R Porte</name></author><author><name sortKey="Fougeron, D" uniqKey="Fougeron D">D Fougeron</name></author><author><name sortKey="Mu Oz Wolf, N" uniqKey="Mu Oz Wolf N">N Muñoz-Wolf</name></author><author><name sortKey="Tabareau, J" uniqKey="Tabareau J">J Tabareau</name></author><author><name sortKey="Georgel, Af" uniqKey="Georgel A">AF Georgel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tanaka, A" uniqKey="Tanaka A">A Tanaka</name></author><author><name sortKey="Nakamura, S" uniqKey="Nakamura S">S Nakamura</name></author><author><name sortKey="Seki, M" uniqKey="Seki M">M Seki</name></author><author><name sortKey="Fukudome, K" uniqKey="Fukudome K">K Fukudome</name></author><author><name sortKey="Iwanaga, N" uniqKey="Iwanaga N">N Iwanaga</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, L" uniqKey="Chen L">L Chen</name></author><author><name sortKey="Guo, S" uniqKey="Guo S">S Guo</name></author><author><name sortKey="Wu, L" uniqKey="Wu L">L Wu</name></author><author><name sortKey="Hao, C" uniqKey="Hao C">C Hao</name></author><author><name sortKey="Xu, W" uniqKey="Xu W">W Xu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Onishi, M" uniqKey="Onishi M">M Onishi</name></author><author><name sortKey="Kitano, M" uniqKey="Kitano M">M Kitano</name></author><author><name sortKey="Taniguchi, K" uniqKey="Taniguchi K">K Taniguchi</name></author><author><name sortKey="Homma, T" uniqKey="Homma T">T Homma</name></author><author><name sortKey="Kobayashi, M" uniqKey="Kobayashi M">M Kobayashi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Walther, E" uniqKey="Walther E">E Walther</name></author><author><name sortKey="Richter, M" uniqKey="Richter M">M Richter</name></author><author><name sortKey="Xu, Z" uniqKey="Xu Z">Z Xu</name></author><author><name sortKey="Kramer, C" uniqKey="Kramer C">C Kramer</name></author><author><name sortKey="Von Grafenstein, S" uniqKey="Von Grafenstein S">S von Grafenstein</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Armstrong, Sm" uniqKey="Armstrong S">SM Armstrong</name></author><author><name sortKey="Mubareka, S" uniqKey="Mubareka S">S Mubareka</name></author><author><name sortKey="Lee, Wl" uniqKey="Lee W">WL Lee</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mathieu, C" uniqKey="Mathieu C">C Mathieu</name></author><author><name sortKey="Rioux, G" uniqKey="Rioux G">G Rioux</name></author><author><name sortKey="Dumas, Mc" uniqKey="Dumas M">MC Dumas</name></author><author><name sortKey="Leclerc, D" uniqKey="Leclerc D">D Leclerc</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Metzger, Dw" uniqKey="Metzger D">DW Metzger</name></author><author><name sortKey="Furuya, Y" uniqKey="Furuya Y">Y Furuya</name></author><author><name sortKey="Salmon, Sl" uniqKey="Salmon S">SL Salmon</name></author><author><name sortKey="Roberts, S" uniqKey="Roberts S">S Roberts</name></author><author><name sortKey="Sun, K" uniqKey="Sun K">K Sun</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Klugman, Kp" uniqKey="Klugman K">KP Klugman</name></author><author><name sortKey="Chien, Yw" uniqKey="Chien Y">YW Chien</name></author><author><name sortKey="Madhi, Sa" uniqKey="Madhi S">SA Madhi</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">101682673</journal-id><journal-id journal-id-type="pubmed-jr-id">45264</journal-id><journal-id journal-id-type="nlm-ta">J Infect Pulm Dis</journal-id><journal-id journal-id-type="iso-abbrev">J Infect Pulm Dis</journal-id><journal-title-group><journal-title>Journal of infectious pulmonary diseases</journal-title></journal-title-group><issn pub-type="epub">2470-3176</issn></journal-meta><article-meta><article-id pub-id-type="pmid">27981251</article-id><article-id pub-id-type="pmc">5154682</article-id><article-id pub-id-type="manuscript">NIHMS784378</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Lethal Synergism between Influenza and <italic>Streptococcus pneumoniae</italic></article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Rudd</surname><given-names>Jennifer M</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Ashar</surname><given-names>Harshini K</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Chow</surname><given-names>Vincent TK</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Teluguakula</surname><given-names>Narasaraju</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib></contrib-group><aff id="A1"><label>1</label>Center for Veterinary Health Sciences, Oklahoma State University, OK, USA</aff><aff id="A2"><label>2</label>Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore</aff><author-notes><corresp id="cor1"><label>*</label><bold>Corresponding author:</bold> Narasaraju Teluguakula, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK, USA, <email>narasa@okstate.edu</email></corresp></author-notes><pub-date pub-type="nihms-submitted"><day>19</day><month>5</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>30</day><month>4</month><year>2016</year></pub-date><pub-date pub-type="ppub"><month>10</month><year>2016</year></pub-date><pub-date pub-type="pmc-release"><day>13</day><month>12</month><year>2016</year></pub-date><volume>2</volume><issue>2</issue><elocation-id>10.16966/2470-3176.114</elocation-id><permissions><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><abstract><p id="P1">The devastating synergism of bacterial pneumonia with influenza viral infections left its mark on the world over the last century. Although the details of pathogenesis remain unclear, the synergism is related to a variety of factors including pulmonary epithelial barrier damage which exposes receptors that influence bacterial adherence and the triggering of an exaggerated innate immune response and cytokine storm, which further acts to worsen the injury. Several therapeutics and combination therapies of antibiotics, anti-inflammatories including corticosteroids and toll-like receptor modifiers, and anti-virals are being discussed. This mini review summarizes recent developments in unearthing the pathogenesis of the lethal synergism of pneumococcal co-infection following influenza, as well as addresses potential therapeutic options and combinations of therapies currently being evaluated.</p></abstract><kwd-group><kwd>Bacterial co-infection</kwd><kwd>Influenza</kwd><kwd><italic>Streptococcus pneumoniae</italic></kwd><kwd>Pathogenesis</kwd><kwd>Therapeutics</kwd></kwd-group></article-meta></front><body><sec id="S1"><title>Pandemic Co-infection: A History of Influenza Pandemics and Secondary Bacterial Pneumonia</title><p id="P2">Beginning in 1918, as World War I was coming to a close, influenza pandemic occurred resulting in an estimated 50 million deaths worldwide [<xref rid="R1" ref-type="bibr">1</xref>–<xref rid="R4" ref-type="bibr">4</xref>]. In just a few short years, the pandemic had killed well over double the number of people who had died due to World War I. Termed the “Spanish Flu”, this pandemic resulted in excessive mortality well beyond the expected seasonal influenza and targeted young, otherwise healthy adults with a swiftly deadly disease course [<xref rid="R1" ref-type="bibr">1</xref>,<xref rid="R5" ref-type="bibr">5</xref>]. Based on preserved lung tissue sections and autopsy analyses, 95% of these deaths were attributed to co-infections during the 1918 flu pandemic [<xref rid="R5" ref-type="bibr">5</xref>,<xref rid="R6" ref-type="bibr">6</xref>]. Since 1918, three more influenza pandemics have occurred, two with disproportionate rates of mortality. The H2N2 “Asian Flu” pandemic of 1957–1958 and the H3N2 “Hong Kong” Flu of 1968 [<xref rid="R7" ref-type="bibr">7</xref>]. In 1968, the Hong Kong Flu hit the world in two waves-the first causing excessive mortality in North America, and the second wave affecting Europe, Asia and Africa between 1968 and 1970 [<xref rid="R8" ref-type="bibr">8</xref>,<xref rid="R9" ref-type="bibr">9</xref>]. More recently, in 2009, the triple reassortment H1N1 virus, termed the “Swine Flu”, had killed roughly 285,400 people worldwide by its completion in 2010 [<xref rid="R2" ref-type="bibr">2</xref>,<xref rid="R5" ref-type="bibr">5</xref>]. Throughout all these pandemics, co-infections continued to play key role in lethality, making it crucial to consider these bacterial co-pathogens when planning for a pandemic [<xref rid="R10" ref-type="bibr">10</xref>,<xref rid="R11" ref-type="bibr">11</xref>].</p><p id="P3">In an extensive review of influenza and bacterial co-infections from the 20<sup>th</sup> century, several more common pathogens were identified including <italic>Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus spp</italic>. (in particular <italic>S. aureus</italic>), and other <italic>Streptococcus spp.</italic> [<xref rid="R12" ref-type="bibr">12</xref>]. Beyond the threat of high rates co-infections in pandemics, bacterial-super infections also contribute to about 65,000 deaths by seasonal influenza virus infections every year in the United States [<xref rid="R2" ref-type="bibr">2</xref>,<xref rid="R12" ref-type="bibr">12</xref>], although the rates of bacterial co-infections were found to be considerably higher during a pandemic than during the seasonal influenza period-of those bacterial co-infections, 41% were identified as <italic>S. pneumoniae</italic>, followed by 25% <italic>Staphylococcus spp.</italic>, 16% other <italic>Streptococcus spp.</italic>, and about 13% <italic>H. influenza</italic> [<xref rid="R12" ref-type="bibr">12</xref>]. Despite <italic>S. pneumoniae</italic> emerging as the predominant strain in 1918, during the 1957 pandemic, the clinical presentation of the disease shifted to a fulminant pneumonia with severe pulmonary edema and hemorrhage resulting in rapid death. This was soon attributed to principal co-infection with <italic>S. aureus</italic> [<xref rid="R13" ref-type="bibr">13</xref>]. By the following pandemic in the late 1960’s, <italic>S. pneumoniae</italic> had again emerged as the predominant bacterial co-pathogen.</p><p id="P4"><italic>S. pneumoniae</italic>, also termed pneumococcus, is a gram-positive diplococci that commonly colonize the upper respiratory tract of 20–50% of healthy children and 8–30% of healthy adults [<xref rid="R14" ref-type="bibr">14</xref>]. Although generally asymptomatic when colonizing the nasopharynx, pneumococcus is also the most frequently seen bacterial agent in bacterial meningitis, otitis media, sepsis and all community-acquired pneumonia [<xref rid="R14" ref-type="bibr">14</xref>] and is correlated with an increase in intensive care unit hospitalizations and death [<xref rid="R2" ref-type="bibr">2</xref>]. Pneumococcal disease is difficult to classify because of the diverse nature of its various strains and serotypes which affect disease outcomes, co-infection models and transmission [<xref rid="R15" ref-type="bibr">15</xref>]. Pneumococci can express one of over 90 capsule types which greatly alter their pathogenicity, and makes development of effective vaccines and therapies difficult [<xref rid="R15" ref-type="bibr">15</xref>–<xref rid="R17" ref-type="bibr">17</xref>]. Diagnosis is also quite difficult, as many of the bacterial pathogens seen in co-infection, <italic>S. pneumoniae</italic> in particular, regularly colonizes the nasopharynx [<xref rid="R1" ref-type="bibr">1</xref>]. As the predominant co-pathogen in influenza co-infection, this mini review will focus on the proposed contributors to the pathogenesis of the synergistic co-infection of <italic>S. pneumoniae</italic> with influenza, as well as several therapeutic options being considered at this time.</p></sec><sec id="S2"><title>The Complexity of Co-infection: Why are Influenza Viruses and <italic>Streptococcus pneumoniae</italic> Lethally Synergistic?</title><sec id="S3"><title>Pulmonary epithelial barrier damage</title><p id="P5">It has been shown that mice exposed to influenza have hyper inflammatory responses with increased bacterial burdens and decreased pulmonary clearance of <italic>S. pneumoniae</italic> following co-infection compared to controls [<xref rid="R18" ref-type="bibr">18</xref>]. Although the exact mechanisms behind the lethal synergism seen with co-infection remain unclear, numerous causative pathways and pathology have been researched to establish the connection. Influenza infection damages the host by causing alveolar epithelial damage, surfactant disruption and resultant obstruction of small airways by sloughed cells, mucus and other debris [<xref rid="R14" ref-type="bibr">14</xref>,<xref rid="R19" ref-type="bibr">19</xref>]. The damage to the respiratory epithelium leads to exposure of the underlying basement membrane and progenitor epithelial cells, resulting in an inability of the respiratory epithelium to repair itself and re-proliferate [<xref rid="R20" ref-type="bibr">20</xref>]. As epithelial damage is worsened, a rise in lethality, likely due to bacteremia, is appreciated [<xref rid="R20" ref-type="bibr">20</xref>,<xref rid="R21" ref-type="bibr">21</xref>]. Exposure of the basement membrane and fibrin also increase bacterial adherence [<xref rid="R4" ref-type="bibr">4</xref>]. Pandemic viral infections inflict high cytotoxicity on the alveolar epithelium, which could possibly contribute to the increase in proportions of co-infections seen at these times [<xref rid="R2" ref-type="bibr">2</xref>,<xref rid="R20" ref-type="bibr">20</xref>]. In addition, influenza infection also causes a decrease in mucociliary clearance and coordination, resulting in failure of removal of bacteria prior to the adherence to the damaged surfaces in the lung [<xref rid="R14" ref-type="bibr">14</xref>].</p></sec><sec id="S4"><title>Receptor exposure and bacterial adherence</title><p id="P6">The desialylation by influenza viral neuraminidase also participates in bacterial adherence to epithelial cells. Sialylated mucins act as decoy receptors for the bacteria [<xref rid="R1" ref-type="bibr">1</xref>,<xref rid="R3" ref-type="bibr">3</xref>,<xref rid="R4" ref-type="bibr">4</xref>,<xref rid="R22" ref-type="bibr">22</xref>]. The effects that co-infection has on the recognition of microbial glycans by lectins enhances this pneumococcal adhesion, making patients with influenza more susceptible to secondary pneumonia [<xref rid="R22" ref-type="bibr">22</xref>]. Damage of epithelial cells also expose glycanson their surface, thus enhancing bacterial adherence [<xref rid="R22" ref-type="bibr">22</xref>]. A variety of proteins are altered and displayed on epithelial cells following influenza virus infections, such as platelet activating factor receptor (PAFr), that promote bacterial adherence and disease [<xref rid="R1" ref-type="bibr">1</xref>,<xref rid="R23" ref-type="bibr">23</xref>]. Pneumococci also have a variety of virulence factors that allow adherence to these newly exposed receptors on damaged epithelium, laminin and fibrin, including pneumococcal surface protein A (PsaP) and pneumococcal serine-rich repeat protein (PsrP) [<xref rid="R16" ref-type="bibr">16</xref>]. PsaP is a lipoprotein pneumococcal antigen that aids in adherence to nasopharyngeal epithelial cells via E-cadherin, while PsrP is a lung-specific adherin [<xref rid="R24" ref-type="bibr">24</xref>].</p></sec><sec id="S5"><title>The innate response: can you have too much of a good thing?</title><p id="P7">Several studies have highlighted exaggerated immune responses in contributing to the synergism during bacterial co-infection. Among innate immune cells, high neutrophil influx has been linked with increased immunopathology in bacterial super infections following influenza (<xref ref-type="fig" rid="F1">Figure 1</xref>) [<xref rid="R25" ref-type="bibr">25</xref>]. Neutrophils are short lived and terminally differentiated cells, primarily involved in phagocytic clearance of the bacteria. The ingested bacteria are destroyed through the generation of potent oxidants after activation of the NADPH oxidase complex (respiratory burst) or by lytic enzymes and antimicrobial peptides within the phagolysosome. After bacterial co-infection, neutrophil numbers become excessive within hours, but macrophages and dendritic cells do not share the same disproportionate increase [<xref rid="R26" ref-type="bibr">26</xref>]. Myeloperoxidase measurements do not increase at the same rate as the neutrophil quantity, suggesting that these rapidly recruited neutrophils will not have the same antibacterial function that the initial responders did [<xref rid="R26" ref-type="bibr">26</xref>]. Functional impairment of neutrophils is seen through several capacities. Phagocytosis has been shown to be decreased in both neutrophils and macrophages following influenza infection [<xref rid="R25" ref-type="bibr">25</xref>,<xref rid="R26" ref-type="bibr">26</xref>] and several pathways to this reduction have been evaluated including resistance to phagocytic granule components [<xref rid="R27" ref-type="bibr">27</xref>], and the down regulation of the MARCO receptor due to interferon production [<xref rid="R4" ref-type="bibr">4</xref>,<xref rid="R28" ref-type="bibr">28</xref>,<xref rid="R29" ref-type="bibr">29</xref>]. Neutrophils and macrophages also have a marked decrease in reactive oxygen species following co-infection [<xref rid="R29" ref-type="bibr">29</xref>]. These cells can kill pathogens through oxidative burst, which creates toxic reactive oxygen species through NADPH oxidase complex or myeloperoxidase. Gram positive bacteria such as <italic>S. pneumoniae</italic> can have a bacterial superoxide dismutase that can protect the pathogen from these toxic species [<xref rid="R27" ref-type="bibr">27</xref>].</p><p id="P8">Neutrophils can potentially cause worsened inflammatory disease through the release of neutrophil extracellular traps (NETs). We have previously shown that excessive neutrophils and NETs contribute to alveolar-capillary damage after influenza challenge in mice. NETs formation is dependent on redox enzyme activities [<xref rid="R30" ref-type="bibr">30</xref>]. NETs were first identified as a process of cell death that released DNA, histones and granular proteins such as elastase and myeloperoxidase to entrap and kill pathogens [<xref rid="R31" ref-type="bibr">31</xref>]. Since the initial identification of NETs, they have also been shown to be detrimental to the host-particularly through histones which induce endothelial and epithelial cell damage and worsened disease [<xref rid="R32" ref-type="bibr">32</xref>]. Further, using pneumococcal super infection following influenza, an extensive accumulation of NETs was recognized, especially in the damaged areas of the lungs, indicating their potential role in tissue injury. Moreover, NETs released during pneumococcal super infection did not show any bactericidal or fungicidal activities [<xref rid="R33" ref-type="bibr">33</xref>,<xref rid="R34" ref-type="bibr">34</xref>]. Our recent studies have shown that NETs generation is dependent on the pneumococcal capsule thickness and varies with the different serotype infections. The increase in thickness of the capsule results in enhanced tissue damage and lung pathology [<xref rid="R17" ref-type="bibr">17</xref>]. NETs have been identified in various inflammatory disease models other than pneumococcal pulmonary co-infection such as co-infection of otitis media and sepsis [<xref rid="R35" ref-type="bibr">35</xref>,<xref rid="R36" ref-type="bibr">36</xref>]. Although the complete pathway for NETs induction has yet to be discovered, <italic>S. pneumoniae</italic> has been shown to induce NETs through an enzyme called α-enolasae [<xref rid="R37" ref-type="bibr">37</xref>]. Paradoxically, a pneumococcal endonuclease, EndA, has been identified as an important virulence factor through its ability to degrade NETs and diminish their bactericidal response [<xref rid="R38" ref-type="bibr">38</xref>]. As with many other areas of the complex pathogenesis of co-infection, it appears that NETs too must be balanced between positive effects and those that are detrimental to the host.</p><p id="P9">Apoptosis of various cell types also appears to be affected by bacterial co-infection after influenza. Monocytes express a TNF-related apoptosis-inducing ligand (TRAIL) that can be blocked through CCR2 blockage and result in decreased bacterial load and protection if administered prior to co-infection [<xref rid="R39" ref-type="bibr">39</xref>]. <italic>In vitro</italic>, influenza virus has been shown to accelerate neutrophil apoptosis by enhancing Fas expression and activating caspase, decreasing neutrophil survival [<xref rid="R40" ref-type="bibr">40</xref>]. The significant neutrophil influx triggered by various viral and bacterial toxins such as PB1-F2 in a co-infection result in a cytokine storm and can lead to a severely damaging hyper inflammatory response which can be seen histopathologically as excessive neutrophilia, sloughing epithelium, hemorrhage, obstructed airways, pleuritic and large areas of lung consolidation [<xref rid="R26" ref-type="bibr">26</xref>].</p></sec><sec id="S6"><title>Toll-like receptors and their contribution to immunopathology and interferon signaling</title><p id="P10">Toll-like receptors are an important part of the innate immune response and recognize conserved patterns in a variety of pathogens. Upon recognition, these receptors trigger a series of events resulting in activation of the innate immune response through production of various pro-inflammatory chemokines, cytokines, interferons and recruitment of those innate responders such as the neutrophils and macrophages [<xref rid="R41" ref-type="bibr">41</xref>]. In particular, these TLRs can recognize cellular wall components of gram-positive organisms, such as those in <italic>S. pneumoniae</italic> [<xref rid="R42" ref-type="bibr">42</xref>]. Influenza induces expression of toll-like receptors, such as TLR3 which acts to recognize RNA and DNA of pathogens after phagocytosis, and this not only sensitizes cells to secondary infection with pneumococcal pneumonia, but also decreases bacterial clearance and increases type I interferons, which have been shown to negatively affect survival in a murine model [<xref rid="R43" ref-type="bibr">43</xref>,<xref rid="R44" ref-type="bibr">44</xref>]. In addition to impairment of phagocytosis, production of interferons after recognition of pathogens by TLRs plays a large role in pathogenesis of co-infection as well. Type I and II interferons are produced following recognition of viral nucleic acids by toll-like receptors (TLRs) [<xref rid="R1" ref-type="bibr">1</xref>]. The induction of type I interferon during a primary nonlethal influenza infection was shown to be sufficient to promote lethality with co-infection of <italic>S. pneumoniae</italic> [<xref rid="R45" ref-type="bibr">45</xref>]. In addition, mice deficient in type I interferon receptor signaling has improved survival and bacterial clearance [<xref rid="R46" ref-type="bibr">46</xref>]. One mechanism by which type I interferon release in response to influenza infection results in worsened bacterial super infection is through the suppression of γδ T cell production of interleukin-17 (IL-17) [<xref rid="R45" ref-type="bibr">45</xref>]. γδ T cells in the lung act as specialized innate responders and normally produce the majority of IL-17 in response to a variety of viral and bacterial infections [<xref rid="R45" ref-type="bibr">45</xref>,<xref rid="R47" ref-type="bibr">47</xref>,<xref rid="R48" ref-type="bibr">48</xref>] which can suppress the effects of bacterial super infection. If type I interferon signaling is up regulated and IL-17 production suppressed through decreased γδ T cell function, bacterial colonization in the lungs is increased causing in deteriorated pathology and disease [<xref rid="R45" ref-type="bibr">45</xref>]. With interferon signaling increase, an impaired production of the neutrophil attractants CXCL1 and CXCL2 was noted following co-infection. This may explain some of the impaired neutrophil response to the early phase of co-infection [<xref rid="R46" ref-type="bibr">46</xref>]. Pneumolysin, a cytolytic toxin of <italic>S. pneumoniae</italic>, induces substantial inflammation through activation of TLR4 [<xref rid="R49" ref-type="bibr">49</xref>]. TLR2 is also an important mediator of the damage associated with pneumococcal pneumonia [<xref rid="R50" ref-type="bibr">50</xref>]. As discussed, the innate immune response is necessary early in the disease course, but can result in worsened pathology if the response remains elevated for too long. Identifying the pathways most involved in this synergism and filling in the gaps with the pathology of the disease will not only improve our general knowledge in all co-infections, but, more importantly help identify therapeutic targets to improve clinical outcome in those affected.</p></sec></sec><sec id="S7"><title>Current Prospective Therapeutics and the Efficacy of Combination Therapies</title><sec id="S8"><title>Antibiotics and combination therapies</title><p id="P11">Due to the complex nature of co-infection, a wide variety of therapeutic options and combinations of therapy are being evaluated for efficacy in a dual infection model of influenza A virus with subsequent pneumococcal infection. Combination therapies suggest the best results at this time, with one element of the combination being antibiotic therapy. Several classes of antibiotics have been evaluated. Although β-lactams were initially considered a mainstay of treatment for pneumococcal pneumonia, it has been shown well over the last decade that standalone therapies are no longer ideal and that combinations with macrolides and fluoroquinolones are more effective, especially in light of emerging antibiotic resistance [<xref rid="R51" ref-type="bibr">51</xref>–<xref rid="R53" ref-type="bibr">53</xref>]. Macrolides such as azithromycin and clarithromycin are bacteriostatic and work by binding the 50S ribosomal subunit, thereby inhibiting protein synthesis. In addition to their antimicrobial effects, macrolides also have an immunomodulatory effect, which poses an additional benefit in combatting superinfections. Azithromycin in particular has been shown to improve survival in a mouse model of influenza and pneumococcal dual infection with almost double the survival rate than ampicillin (92% versus 56%) as well as improved outcomes over clindamycin [<xref rid="R54" ref-type="bibr">54</xref>]. Combination ampicillin and azithromycin for treatment of pneumococcal pneumonia not only decreases lung inflammation, but also decreases pulmonary vascular permeability and increases bacterial clearance, limiting the chances of septicemia [<xref rid="R55" ref-type="bibr">55</xref>]. A lower number of inflammatory cells and proinflammatory cytokines are seen with macrolide treatment than standalone β-lactams as well as less severe lung histopathology-as this antibiotic is bacteriostatic, the reduction in an otherwise exacerbated inflammatory response seen with β-lactam therapy may be due to lessening in bacterial lysis [<xref rid="R50" ref-type="bibr">50</xref>,<xref rid="R54" ref-type="bibr">54</xref>]. Another study comparing the effects of moxifloxacin, a bactericidal drug, with azithromycin in a murine model of acute bacterial rhinosinusitis supports this as the azithromycin treatment resulted in rapid bacterial clearance and reduced inflammation compared with the relatively limited effect of moxifloxacin [<xref rid="R56" ref-type="bibr">56</xref>]. Further evaluation of the potential negative effects of azithromycin in human disease is still needed, but a 2015 study evaluating cardiotoxicity of azithromycin in community-acquired pneumonia (CAP) showed that the QT prolongation suggested to be an adverse effect of therapy was not associated with treatment, but instead with the disease of pneumonia, regardless of the therapy administered [<xref rid="R57" ref-type="bibr">57</xref>].</p></sec><sec id="S9"><title>Anti-inflammatories</title><p id="P12">The use of corticosteroids in treatment of bacterial infections is always a hot topic and one heavily debated. On the one hand, some argue that the use of an immune inhibitor in combination with an antibiotic to reduce the bacterial burden can more effectively control the exaggerated inflammatory response seen in co-infection and that the use of steroids should improve survival rates. In a murine model, this seems to hold true-a susceptible murine model for the 2009 H1N1 pandemic showed that dexamethasone significantly improved survival rate and acute lung injury [<xref rid="R58" ref-type="bibr">58</xref>]. A reduction in the proinflammatory cytokine storm, and improved clinical outcomes was associated with combination treatment of dexamethasone and azithromycin in mice [<xref rid="R26" ref-type="bibr">26</xref>]. However, what is most concerning with corticosteroids was highlighted in a retrospective cohort study from 2011 in which the early use of glucocorticoids was significantly linked with the development of more severe disease versus patients who did not receive the drug in pandemic H1N1 [<xref rid="R59" ref-type="bibr">59</xref>]. The <italic>in vivo</italic> benefits in human disease, particularly in a pandemic setting, are clearly still up for debate.</p><p id="P13">Toll-like receptor agonists and antagonists are a relatively new area showing promise as a potential combination therapeutic for pneumococcal co-infection. Special attention has been given to TLR2, which has been shown to mediate the extensive tissue damage, lung necrosis and mortality seen after bactericidal treatment of pneumococcal pneumonia in a murine co-infection model [<xref rid="R50" ref-type="bibr">50</xref>]. This mediation was independent of TLR4 or the pneumococcal virulence factor, pneumolysin. TLR2 also plays a role in transmission of disease, likely with a multitude of other factors-when a TLR2 agonist (Pam3Cys) was administered in a murine model of co-infection, contact transmission was diminished as well as inflammation and bacterial shedding [<xref rid="R41" ref-type="bibr">41</xref>]. A TLR2 agonist was again seen to reduce the severity of pneumococcal infection post-influenza in a murine model by decreasing bacterial loads and pro-inflammatory cytokines, subsequently leading to decreased vascular permeability and reduced bacteremia [<xref rid="R60" ref-type="bibr">60</xref>]. Macrophage-activating lipopeptide 2 (MALP-2) is a TLR2/6 agonist that, when administered prior to pneumococcal co-infection, increases proinflammatory cytokine and chemokine release and enhances neutrophil recruitment without creating excessive inflammation, so also reduces bacterial loads and improves survival [<xref rid="R61" ref-type="bibr">61</xref>]. Like TLR2 agonists, TLR5, or flagellin, agonists also act as immunostimulants. Given in combination with an antibiotic, flagellin will decrease bacterial load and boost antibiotic activity by stimulating CXCL1 to recruit neutrophils and reduce bacteremia [<xref rid="R62" ref-type="bibr">62</xref>]. TLR3 also participates in the immunostimulatory response when stimulated by pneumococcal RNA. TLR3 acts through TRIF to secrete IL-12. In a co-infection, influenza virus up regulates TLR3 in dendritic cells, which helps prime the cells for recognition of pneumococcal disease [<xref rid="R43" ref-type="bibr">43</xref>]. In another study, a TLR4 agonist, UT12, showed promise in improving clinical outcome and disease in a murine coinfection model after hastening the macrophage recruitment response [<xref rid="R63" ref-type="bibr">63</xref>]. Modulating TLRs is an interesting approach to understanding the pathogenesis of co-infection and, with further evaluation, may provide some promising combination therapies to attempt. The timing of therapy and its clinical relevance should still be carefully considered, as this therapy is effective when administered after influenza infection, but prior to secondary infection.</p><p id="P14">The role of γδ T cells in interferon signaling and IL-17 production is also being explored as a therapeutic for bacterial super infections. Since super infected mice inhibit IL-17, resulting in worsened bacterial replication and disease, the administration of recombinant IL-17 in these mice has improved bacterial clearance indicating that induction of IL-17 remains a potential novel therapy [<xref rid="R45" ref-type="bibr">45</xref>]. In a recent study, recombinant IL-17F was administered just prior to <italic>S. pneumoniae</italic> infection in a murine model and the therapy resulted in decreased bacterial colonization in the lungs [<xref rid="R64" ref-type="bibr">64</xref>]. In general, modulation of IFN-I signaling, IL-17 production and the function of γδ T cells all remain intriguing areas of study for treatment of dual infections.</p></sec><sec id="S10"><title>Other potential therapeutics</title><p id="P15">Multiple other therapies are being evaluated as well. Anti-virals are a mainstay of treatment and many are looking for alternatives to oseltamivir. Peramivir is a neuraminidase inhibitor that reduced mortality in co-infected mice better than oseltamivir by inhibiting viral replication resulting in improved bacterial clearance and survival [<xref rid="R65" ref-type="bibr">65</xref>]. Although oseltamivir has shown effectiveness to both viral and bacterial neuraminidase, peramivir only seems to inhibit viral neuraminidase [<xref rid="R65" ref-type="bibr">65</xref>,<xref rid="R66" ref-type="bibr">66</xref>]. Another neuraminidase inhibiting compound, artocarpin, was shown to have a bactericidal effect <italic>in vitro</italic>, reducing pneumococcal viability by a factor of over 1000, and reduced biofilm formation [<xref rid="R66" ref-type="bibr">66</xref>]. Several agents to reduce vascular leakage have also been evaluated with varying effectiveness including Slit2N, vasculotide, atrial natriuretic peptide, S1P, activated protein C, and doxycycline [<xref rid="R21" ref-type="bibr">21</xref>,<xref rid="R67" ref-type="bibr">67</xref>]. Mathieu, et al. [<xref rid="R68" ref-type="bibr">68</xref>] has started evaluating the use of nanoparticles carrying a plant virus coat protein and ssRNA that trigger a strong innate immune response in the lung during a co-infection. Vaccinations are also a key area of research, especially when considering the effect these vaccinations may have in pandemic preparedness. Pneumococcal capsular polysaccharide conjugate vaccines have been shown to be very effective (100%) against otherwise lethal pneumococcal disease, but in co-infection, the results are not as promising with less than 40% survival with vaccination in a murine model [<xref rid="R69" ref-type="bibr">69</xref>]. The value of the current vaccine is evident already though, with the vaccine being 84–94% efficacious against the serotypes included and reducing the severity of disease and risk for hospitalization in those affected [<xref rid="R4" ref-type="bibr">4</xref>]. In the U.S. alone, we have seen a 39% reduction in clinical pneumonia in children since the vaccine has been introduced [<xref rid="R70" ref-type="bibr">70</xref>]. Imagine how effective the current vaccine will be once it’s more available in developing countries.</p></sec></sec><sec sec-type="conclusions" id="S11"><title>Conclusions</title><p id="P16">Co-infection of <italic>S. pneumoniae</italic> with influenza promises to be a relevant disease for many years to come. Despite the many recent advances in our knowledge base regarding the disease, the complexity of pathogenesis implies that an effective “shotgun” approach to therapy is doubtful and a fine-tuned combination of antimicrobial agents with immunomodulators is likely to be more effective when treating the disease. Because of the expansive diversity in both influenza viral strains and pneumococcal disease and their ever-changing patterns of resistance and survival, therapy effective for one combination may not consistently work for all. This review touches on a few approaches to consider in therapeutic design, but continued discovery will be needed to better prepare for the next pandemic.</p></sec></body><back><ack id="S12"><p id="P17">This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number P20GM103648. We are thankful to Mr. Benton Rudd for his assistance in the preparation of the Figure.</p></ack><ref-list><title>References</title><ref id="R1"><label>1</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>McCullers</surname><given-names>JA</given-names></name></person-group><article-title>The co-pathogenesis of influenza viruses with bacteria in the lung</article-title><source>Nat Rev Microbiol</source><year>2014</year><volume>12</volume><fpage>252</fpage><lpage>262</lpage><pub-id pub-id-type="pmid">24590244</pub-id></element-citation></ref><ref id="R2"><label>2</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chertow</surname><given-names>DS</given-names></name><name><surname>Memoli</surname><given-names>MJ</given-names></name></person-group><article-title>Bacterial coinfection in influenza: a grand rounds review</article-title><source>JAMA</source><year>2013</year><volume>309</volume><fpage>275</fpage><lpage>282</lpage><pub-id pub-id-type="pmid">23321766</pub-id></element-citation></ref><ref id="R3"><label>3</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kash</surname><given-names>JC</given-names></name><name><surname>Taubenberger</surname><given-names>JK</given-names></name></person-group><article-title>The role of viral, host, and secondary bacterial factors in influenza pathogenesis</article-title><source>Am J Pathol</source><year>2015</year><volume>185</volume><fpage>1528</fpage><lpage>1536</lpage><pub-id pub-id-type="pmid">25747532</pub-id></element-citation></ref><ref id="R4"><label>4</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Madhi</surname><given-names>SA</given-names></name><name><surname>Schoub</surname><given-names>B</given-names></name><name><surname>Klugman</surname><given-names>KP</given-names></name></person-group><article-title>Interaction between influenza virus and <italic>Streptococcus pneumoniae</italic> in severe pneumonia</article-title><source>Expert Rev Respir Med</source><year>2008</year><volume>2</volume><fpage>663</fpage><lpage>672</lpage><pub-id pub-id-type="pmid">20477301</pub-id></element-citation></ref><ref id="R5"><label>5</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rynda-Apple</surname><given-names>A</given-names></name><name><surname>Robinson</surname><given-names>KM</given-names></name><name><surname>Alcorn</surname><given-names>JF</given-names></name></person-group><article-title>Influenza and Bacterial Superinfection: Illuminating the Immunologic Mechanisms of Disease</article-title><source>Infect Immun</source><year>2015</year><volume>83</volume><fpage>3764</fpage><lpage>3770</lpage><pub-id pub-id-type="pmid">26216421</pub-id></element-citation></ref><ref id="R6"><label>6</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Morens</surname><given-names>DM</given-names></name><name><surname>Taubenberger</surname><given-names>JK</given-names></name><name><surname>Fauci</surname><given-names>AS</given-names></name></person-group><article-title>Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness</article-title><source>J Infect Dis</source><year>2008</year><volume>198</volume><fpage>962</fpage><lpage>970</lpage><pub-id pub-id-type="pmid">18710327</pub-id></element-citation></ref><ref id="R7"><label>7</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Viboud</surname><given-names>C</given-names></name><name><surname>Simonsen</surname><given-names>L</given-names></name><name><surname>Fuentes</surname><given-names>R</given-names></name><name><surname>Flores</surname><given-names>J</given-names></name><name><surname>Miller</surname><given-names>MA</given-names></name><etal></etal></person-group><article-title>Global Mortality Impact of the 1957–1959 Influenza Pandemic</article-title><source>J Infect Dis</source><year>2016</year><volume>213</volume><fpage>738</fpage><lpage>745</lpage><pub-id pub-id-type="pmid">26908781</pub-id></element-citation></ref><ref id="R8"><label>8</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Viboud</surname><given-names>C</given-names></name><name><surname>Grais</surname><given-names>RF</given-names></name><name><surname>Lafont</surname><given-names>BA</given-names></name><name><surname>Miller</surname><given-names>MA</given-names></name><name><surname>Simonsen</surname><given-names>L</given-names></name></person-group><article-title>Multinational impact of the 1968 Hong Kong influenza pandemic: evidence for a smoldering pandemic</article-title><source>J Infect Dis</source><year>2005</year><volume>192</volume><fpage>233</fpage><lpage>248</lpage><pub-id pub-id-type="pmid">15962218</pub-id></element-citation></ref><ref id="R9"><label>9</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ortiz</surname><given-names>JR</given-names></name><name><surname>Lafond</surname><given-names>KE</given-names></name><name><surname>Wong</surname><given-names>TA</given-names></name><name><surname>Uyeki</surname><given-names>TM</given-names></name></person-group><article-title>Pandemic influenza in Africa, lessons learned from 1968: a systematic review of the literature</article-title><source>Influenza Other Respir Viruses</source><year>2012</year><volume>6</volume><fpage>11</fpage><lpage>24</lpage><pub-id pub-id-type="pmid">21668669</pub-id></element-citation></ref><ref id="R10"><label>10</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>McCullers</surname><given-names>JA</given-names></name></person-group><article-title>Planning for an influenza pandemic: thinking beyond the virus</article-title><source>J Infect Dis</source><year>2008</year><volume>198</volume><fpage>945</fpage><lpage>947</lpage><pub-id pub-id-type="pmid">18710326</pub-id></element-citation></ref><ref id="R11"><label>11</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gupta</surname><given-names>RK</given-names></name><name><surname>George</surname><given-names>R</given-names></name><name><surname>Nguyen-Van-Tam</surname><given-names>JS</given-names></name></person-group><article-title>Bacterial pneumonia and pandemic influenza planning</article-title><source>Emerg Infect Dis</source><year>2008</year><volume>14</volume><fpage>1187</fpage><lpage>1192</lpage><pub-id pub-id-type="pmid">18680640</pub-id></element-citation></ref><ref id="R12"><label>12</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wang</surname><given-names>XY</given-names></name><name><surname>Kilgore</surname><given-names>PE</given-names></name><name><surname>Lim</surname><given-names>KA</given-names></name><name><surname>Wang</surname><given-names>SM</given-names></name><name><surname>Lee</surname><given-names>J</given-names></name><etal></etal></person-group><article-title>Influenza and bacterial pathogen coinfections in the 20<sup>th</sup> century</article-title><source>Interdiscip Perspect Infect Dis</source><year>2011</year><volume>2011</volume><fpage>146376</fpage><pub-id pub-id-type="pmid">21747847</pub-id></element-citation></ref><ref id="R13"><label>13</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Herzog</surname><given-names>H</given-names></name><name><surname>Staub</surname><given-names>H</given-names></name><name><surname>Richterich</surname><given-names>R</given-names></name></person-group><article-title>Gas-analytical studies in severe pneumonia; observations during the 1957 influenza epidemic</article-title><source>Lancet</source><year>1959</year><volume>1</volume><fpage>593</fpage><lpage>597</lpage><pub-id pub-id-type="pmid">13642816</pub-id></element-citation></ref><ref id="R14"><label>14</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>McCullers</surname><given-names>JA</given-names></name></person-group><article-title>Insights into the interaction between influenza virus and pneumococcus</article-title><source>Clin Microbiol Rev</source><year>2006</year><volume>19</volume><fpage>571</fpage><lpage>582</lpage><pub-id pub-id-type="pmid">16847087</pub-id></element-citation></ref><ref id="R15"><label>15</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>McCullers</surname><given-names>JA</given-names></name><name><surname>McAuley</surname><given-names>JL</given-names></name><name><surname>Browall</surname><given-names>S</given-names></name><name><surname>Iverson</surname><given-names>AR</given-names></name><name><surname>Boyd</surname><given-names>KL</given-names></name><etal></etal></person-group><article-title>Influenza enhances susceptibility to natural acquisition of and disease due to <italic>Streptococcus pneumoniae</italic> in ferrets</article-title><source>J Infect Dis</source><year>2010</year><volume>202</volume><fpage>1287</fpage><lpage>1295</lpage><pub-id pub-id-type="pmid">20822454</pub-id></element-citation></ref><ref id="R16"><label>16</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dockrell</surname><given-names>DH</given-names></name><name><surname>Whyte</surname><given-names>MK</given-names></name><name><surname>Mitchell</surname><given-names>TJ</given-names></name></person-group><article-title>pneumococcal pneumonia: mechanisms of infection and resolution</article-title><source>Chest</source><year>2012</year><volume>142</volume><fpage>482</fpage><lpage>491</lpage><pub-id pub-id-type="pmid">22871758</pub-id></element-citation></ref><ref id="R17"><label>17</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Moorthy</surname><given-names>AN</given-names></name><name><surname>Rai</surname><given-names>P</given-names></name><name><surname>Jiao</surname><given-names>H</given-names></name><name><surname>Wang</surname><given-names>S</given-names></name><name><surname>Tan</surname><given-names>KB</given-names></name><etal></etal></person-group><article-title>Capsules of virulent pneumococcal serotypes enhance formation of neutrophil extracellular traps during in vivo pathogenesis of pneumonia</article-title><source>Oncotarget</source><year>2016</year></element-citation></ref><ref id="R18"><label>18</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>LeVine</surname><given-names>AM</given-names></name><name><surname>Koeningsknecht</surname><given-names>V</given-names></name><name><surname>Stark</surname><given-names>JM</given-names></name></person-group><article-title>Decreased pulmonary clearance of <italic>S. pneumoniae</italic> following influenza A infection in mice</article-title><source>J Virol Methods</source><year>2001</year><volume>94</volume><fpage>173</fpage><lpage>186</lpage><pub-id pub-id-type="pmid">11337052</pub-id></element-citation></ref><ref id="R19"><label>19</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Loosli</surname><given-names>CG</given-names></name><name><surname>Stinson</surname><given-names>SF</given-names></name><name><surname>Ryan</surname><given-names>DP</given-names></name><name><surname>Hertweck</surname><given-names>MS</given-names></name><name><surname>Hardy</surname><given-names>JD</given-names></name><etal></etal></person-group><article-title>The destruction of type 2 pneumocytes by airborne <italic>influenza PR8-A virus</italic>; its effect on surfactant and lecithin content of the pneumonic lesions of mice</article-title><source>Chest</source><year>1975</year><volume>67</volume><fpage>7s</fpage><lpage>14s</lpage><pub-id pub-id-type="pmid">1172777</pub-id></element-citation></ref><ref id="R20"><label>20</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kash</surname><given-names>JC</given-names></name><name><surname>Walters</surname><given-names>KA</given-names></name><name><surname>Davis</surname><given-names>AS</given-names></name><name><surname>Sandouk</surname><given-names>A</given-names></name><name><surname>Schwartzman</surname><given-names>LM</given-names></name><etal></etal></person-group><article-title>Lethal synergism of 2009 pandemic H1N1 influenza virus and <italic>Streptococcus pneumoniae</italic> coinfection is associated with loss of murine lung repair responses</article-title><source>MBio</source><year>2011</year><volume>2</volume><fpage>e00172-11</fpage><pub-id pub-id-type="pmid">21933918</pub-id></element-citation></ref><ref id="R21"><label>21</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Florescu</surname><given-names>DF</given-names></name><name><surname>Kalil</surname><given-names>AC</given-names></name></person-group><article-title>The complex link between influenza and severe sepsis</article-title><source>Virulence</source><year>2014</year><volume>5</volume><fpage>137</fpage><lpage>142</lpage><pub-id pub-id-type="pmid">24253109</pub-id></element-citation></ref><ref id="R22"><label>22</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nita-Lazar</surname><given-names>M</given-names></name><name><surname>Banerjee</surname><given-names>A</given-names></name><name><surname>Feng</surname><given-names>C</given-names></name><name><surname>Amin</surname><given-names>MN</given-names></name><name><surname>Frieman</surname><given-names>MB</given-names></name><etal></etal></person-group><article-title>Desialylation of airway epithelial cells during influenza virus infection enhances pneumococcal adhesion via galectin binding</article-title><source>Mol Immunol</source><year>2015</year><volume>65</volume><fpage>1</fpage><lpage>16</lpage><pub-id pub-id-type="pmid">25597246</pub-id></element-citation></ref><ref id="R23"><label>23</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>McCullers</surname><given-names>JA</given-names></name><name><surname>Rehg</surname><given-names>JE</given-names></name></person-group><article-title>Lethal synergism between influenza virus and <italic>Streptococcus pneumoniae</italic>: characterization of a mouse model and the role of platelet-activating factor receptor</article-title><source>J Infect Dis</source><year>2002</year><volume>186</volume><fpage>341</fpage><lpage>350</lpage><pub-id pub-id-type="pmid">12134230</pub-id></element-citation></ref><ref id="R24"><label>24</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Feldman</surname><given-names>C</given-names></name><name><surname>Anderson</surname><given-names>R</given-names></name></person-group><article-title>Review: current and new generation pneumococcal vaccines</article-title><source>J Infect</source><year>2014</year><volume>69</volume><fpage>309</fpage><lpage>325</lpage><pub-id pub-id-type="pmid">24968238</pub-id></element-citation></ref><ref id="R25"><label>25</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>McNamee</surname><given-names>LA</given-names></name><name><surname>Harmsen</surname><given-names>AG</given-names></name></person-group><article-title>Both influenza-induced neutrophil dysfunction and neutrophil-independent mechanisms contribute to increased susceptibility to a secondary <italic>Streptococcus pneumoniae</italic> infection</article-title><source>Infect Immun</source><year>2006</year><volume>74</volume><fpage>6707</fpage><lpage>6721</lpage><pub-id pub-id-type="pmid">16982840</pub-id></element-citation></ref><ref id="R26"><label>26</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Damjanovic</surname><given-names>D</given-names></name><name><surname>Lai</surname><given-names>R</given-names></name><name><surname>Jeyanathan</surname><given-names>M</given-names></name><name><surname>Hogaboam</surname><given-names>CM</given-names></name><name><surname>Xing</surname><given-names>Z</given-names></name></person-group><article-title>Marked improvement of severe lung immunopathology by influenza-associated pneumococcal superinfection requires the control of both bacterial replication and host immune responses</article-title><source>Am J Pathol</source><year>2013</year><volume>183</volume><fpage>868</fpage><lpage>880</lpage><pub-id pub-id-type="pmid">23831294</pub-id></element-citation></ref><ref id="R27"><label>27</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Okumura</surname><given-names>CY</given-names></name><name><surname>Nizet</surname><given-names>V</given-names></name></person-group><article-title>Subterfuge and sabotage: evasion of host innate defenses by invasive gram-positive bacterial pathogens</article-title><source>Annu Rev Microbiol</source><year>2014</year><volume>68</volume><fpage>439</fpage><lpage>458</lpage><pub-id pub-id-type="pmid">25002085</pub-id></element-citation></ref><ref id="R28"><label>28</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sun</surname><given-names>K</given-names></name><name><surname>Metzger</surname><given-names>DW</given-names></name></person-group><article-title>Inhibition of pulmonary antibacterial defense by interferon-gamma during recovery from influenza infection</article-title><source>Nat Med</source><year>2008</year><volume>14</volume><fpage>558</fpage><lpage>564</lpage><pub-id pub-id-type="pmid">18438414</pub-id></element-citation></ref><ref id="R29"><label>29</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Robinson</surname><given-names>KM</given-names></name><name><surname>Kolls</surname><given-names>JK</given-names></name><name><surname>Alcorn</surname><given-names>JF</given-names></name></person-group><article-title>The immunology of influenza virus-associated bacterial pneumonia</article-title><source>Curr Opin Immunol</source><year>2015</year><volume>34</volume><fpage>59</fpage><lpage>67</lpage><pub-id pub-id-type="pmid">25723597</pub-id></element-citation></ref><ref id="R30"><label>30</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Narasaraju</surname><given-names>T</given-names></name><name><surname>Yang</surname><given-names>E</given-names></name><name><surname>Samy</surname><given-names>RP</given-names></name><name><surname>Ng</surname><given-names>HH</given-names></name><name><surname>Poh</surname><given-names>WP</given-names></name><etal></etal></person-group><article-title>Excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis</article-title><source>Am J Pathol</source><year>2011</year><volume>179</volume><fpage>199</fpage><lpage>210</lpage><pub-id pub-id-type="pmid">21703402</pub-id></element-citation></ref><ref id="R31"><label>31</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Brinkmann</surname><given-names>V</given-names></name><name><surname>Reichard</surname><given-names>U</given-names></name><name><surname>Goosmann</surname><given-names>C</given-names></name><name><surname>Fauler</surname><given-names>B</given-names></name><name><surname>Uhlemann</surname><given-names>Y</given-names></name><etal></etal></person-group><article-title>Neutrophil extracellular traps kill bacteria</article-title><source>Science</source><year>2004</year><volume>303</volume><fpage>1532</fpage><lpage>1535</lpage><pub-id pub-id-type="pmid">15001782</pub-id></element-citation></ref><ref id="R32"><label>32</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Saffarzadeh</surname><given-names>M</given-names></name><name><surname>Juenemann</surname><given-names>C</given-names></name><name><surname>Queisser</surname><given-names>MA</given-names></name><name><surname>Lochnit</surname><given-names>G</given-names></name><name><surname>Barreto</surname><given-names>G</given-names></name><etal></etal></person-group><article-title>Neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones</article-title><source>PLoS One</source><year>2012</year><volume>7</volume><fpage>e32366</fpage><pub-id pub-id-type="pmid">22389696</pub-id></element-citation></ref><ref id="R33"><label>33</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Narayana Moorthy</surname><given-names>A</given-names></name><name><surname>Narasaraju</surname><given-names>T</given-names></name><name><surname>Rai</surname><given-names>P</given-names></name><name><surname>Perumalsamy</surname><given-names>R</given-names></name><name><surname>Tan</surname><given-names>KB</given-names></name><etal></etal></person-group><article-title><italic>In vivo</italic> and <italic>in vitro</italic> studies on the roles of neutrophil extracellular traps during secondary pneumococcal pneumonia after primary pulmonary influenza infection</article-title><source>Front Immunol</source><year>2013</year><volume>4</volume><fpage>56</fpage><pub-id pub-id-type="pmid">23467809</pub-id></element-citation></ref><ref id="R34"><label>34</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Abrams</surname><given-names>ST</given-names></name><name><surname>Zhang</surname><given-names>N</given-names></name><name><surname>Manson</surname><given-names>J</given-names></name><name><surname>Liu</surname><given-names>T</given-names></name><name><surname>Dart</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>Circulating histones are mediators of trauma-associated lung injury</article-title><source>Am J Respir Crit Care Med</source><year>2013</year><volume>187</volume><fpage>160</fpage><lpage>169</lpage><pub-id pub-id-type="pmid">23220920</pub-id></element-citation></ref><ref id="R35"><label>35</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Short</surname><given-names>KR</given-names></name><name><surname>von Köckritz-Blickwede</surname><given-names>M</given-names></name><name><surname>Langereis</surname><given-names>JD</given-names></name><name><surname>Chew</surname><given-names>KY</given-names></name><name><surname>Job</surname><given-names>ER</given-names></name><etal></etal></person-group><article-title>Antibodies mediate formation of neutrophil extracellular traps in the middle ear and facilitate secondary pneumococcal otitis media</article-title><source>Infect Immun</source><year>2014</year><volume>82</volume><fpage>364</fpage><lpage>370</lpage><pub-id pub-id-type="pmid">24191297</pub-id></element-citation></ref><ref id="R36"><label>36</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Czaikoski</surname><given-names>PG</given-names></name><name><surname>Mota</surname><given-names>JM</given-names></name><name><surname>Nascimento</surname><given-names>DC</given-names></name><name><surname>Sônego</surname><given-names>F</given-names></name><name><surname>Castanheira</surname><given-names>FV</given-names></name><etal></etal></person-group><article-title>Neutrophil Extracellular Traps Induce Organ Damage during Experimental and Clinical Sepsis</article-title><source>PLoS One</source><year>2016</year><volume>11</volume><fpage>e0148142</fpage><pub-id pub-id-type="pmid">26849138</pub-id></element-citation></ref><ref id="R37"><label>37</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mori</surname><given-names>Y</given-names></name><name><surname>Yamaguchi</surname><given-names>M</given-names></name><name><surname>Terao</surname><given-names>Y</given-names></name><name><surname>Hamada</surname><given-names>S</given-names></name><name><surname>Ooshima</surname><given-names>T</given-names></name><etal></etal></person-group><article-title>alpha-Enolase of <italic>Streptococcus pneumoniae</italic> induces formation of neutrophil extracellular traps</article-title><source>J Biol Chem</source><year>2012</year><volume>287</volume><fpage>10472</fpage><lpage>10481</lpage><pub-id pub-id-type="pmid">22262863</pub-id></element-citation></ref><ref id="R38"><label>38</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zhu</surname><given-names>L</given-names></name><name><surname>Kuang</surname><given-names>Z</given-names></name><name><surname>Wilson</surname><given-names>BA</given-names></name><name><surname>Lau</surname><given-names>GW</given-names></name></person-group><article-title>Competence-independent activity of pneumococcal EndA [corrected] mediates degradation of extracellular dna and nets and is important for virulence</article-title><source>PLoS One</source><year>2013</year><volume>8</volume><fpage>e70363</fpage><pub-id pub-id-type="pmid">23936195</pub-id></element-citation></ref><ref id="R39"><label>39</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ellis</surname><given-names>GT</given-names></name><name><surname>Davidson</surname><given-names>S</given-names></name><name><surname>Crotta</surname><given-names>S</given-names></name><name><surname>Branzk</surname><given-names>N</given-names></name><name><surname>Papayannopoulos</surname><given-names>V</given-names></name><etal></etal></person-group><article-title>TRAIL+ monocytes and monocyte-related cells cause lung damage and thereby increase susceptibility to influenza-Streptococcus pneumoniae coinfection</article-title><source>EMBO Rep</source><year>2015</year><volume>16</volume><fpage>1203</fpage><lpage>1218</lpage><pub-id pub-id-type="pmid">26265006</pub-id></element-citation></ref><ref id="R40"><label>40</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Engelich</surname><given-names>G</given-names></name><name><surname>White</surname><given-names>M</given-names></name><name><surname>Hartshorn</surname><given-names>KL</given-names></name></person-group><article-title>Neutrophil survival is markedly reduced by incubation with influenza virus and <italic>Streptococcus pneumoniae</italic>: role of respiratory burst</article-title><source>J Leukoc Biol</source><year>2001</year><volume>69</volume><fpage>50</fpage><lpage>56</lpage><pub-id pub-id-type="pmid">11200067</pub-id></element-citation></ref><ref id="R41"><label>41</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Richard</surname><given-names>AL</given-names></name><name><surname>Siegel</surname><given-names>SJ</given-names></name><name><surname>Erikson</surname><given-names>J</given-names></name><name><surname>Weiser</surname><given-names>JN</given-names></name></person-group><article-title>TLR2 signaling decreases transmission of <italic>Streptococcus pneumoniae</italic> by limiting bacterial shedding in an infant mouse Influenza A co-infection model</article-title><source>PLoS Pathog</source><year>2014</year><volume>10</volume><fpage>e1004339</fpage><pub-id pub-id-type="pmid">25166617</pub-id></element-citation></ref><ref id="R42"><label>42</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yoshimura</surname><given-names>A</given-names></name><name><surname>Lien</surname><given-names>E</given-names></name><name><surname>Ingalls</surname><given-names>RR</given-names></name><name><surname>Tuomanen</surname><given-names>E</given-names></name><name><surname>Dziarski</surname><given-names>R</given-names></name></person-group><article-title>Cutting edge: recognition of Gram-positive bacterial cell wall components by the innate immune system occurs via Toll-like receptor 2</article-title><source>J Immunol</source><year>1999</year><volume>163</volume><fpage>1</fpage><lpage>5</lpage><pub-id pub-id-type="pmid">10384090</pub-id></element-citation></ref><ref id="R43"><label>43</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Spelmink</surname><given-names>L</given-names></name><name><surname>Sender</surname><given-names>V</given-names></name><name><surname>Hentrich</surname><given-names>K</given-names></name><name><surname>Kuri</surname><given-names>T</given-names></name><name><surname>Plant</surname><given-names>L</given-names></name><etal></etal></person-group><article-title>Toll-Like Receptor 3/TRIF-Dependent IL-12p70 Secretion Mediated by <italic>Streptococcus pneumoniae</italic> RNA and Its Priming by <italic>Influenza A Virus</italic> Coinfection in Human Dendritic Cells</article-title><source>MBio</source><year>2016</year><volume>7</volume><fpage>e00168-16</fpage><pub-id pub-id-type="pmid">26956584</pub-id></element-citation></ref><ref id="R44"><label>44</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tian</surname><given-names>X</given-names></name><name><surname>Xu</surname><given-names>F</given-names></name><name><surname>Lung</surname><given-names>WY</given-names></name><name><surname>Meyerson</surname><given-names>C</given-names></name><name><surname>Ghaffari</surname><given-names>AA</given-names></name><etal></etal></person-group><article-title>Poly I:C enhances susceptibility to secondary pulmonary infections by grampositive bacteria</article-title><source>PLoS One</source><year>2012</year><volume>7</volume><fpage>e41879</fpage><pub-id pub-id-type="pmid">22962579</pub-id></element-citation></ref><ref id="R45"><label>45</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Li</surname><given-names>W</given-names></name><name><surname>Moltedo</surname><given-names>B</given-names></name><name><surname>Moran</surname><given-names>TM</given-names></name></person-group><article-title>Type I interferon induction during influenza virus infection increases susceptibility to secondary <italic>Streptococcus pneumoniae</italic> infection by negative regulation of gammadelta T cells</article-title><source>J Virol</source><year>2012</year><volume>86</volume><fpage>12304</fpage><lpage>12312</lpage><pub-id pub-id-type="pmid">22951826</pub-id></element-citation></ref><ref id="R46"><label>46</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Shahangian</surname><given-names>A</given-names></name><name><surname>Chow</surname><given-names>EK</given-names></name><name><surname>Tian</surname><given-names>X</given-names></name><name><surname>Kang</surname><given-names>JR</given-names></name><name><surname>Ghaffari</surname><given-names>A</given-names></name><etal></etal></person-group><article-title>Type I IFNs mediate development of postinfluenza bacterial pneumonia in mice</article-title><source>J Clin Invest</source><year>2009</year><volume>119</volume><fpage>1910</fpage><lpage>1920</lpage><pub-id pub-id-type="pmid">19487810</pub-id></element-citation></ref><ref id="R47"><label>47</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>O’Brien</surname><given-names>RL</given-names></name><name><surname>Roark</surname><given-names>CL</given-names></name><name><surname>Jin</surname><given-names>N</given-names></name><name><surname>Aydintug</surname><given-names>MK</given-names></name><name><surname>French</surname><given-names>JD</given-names></name><etal></etal></person-group><article-title>gammadelta T-cell receptors: functional correlations</article-title><source>Immunol Rev</source><year>2007</year><volume>215</volume><fpage>77</fpage><lpage>88</lpage><pub-id pub-id-type="pmid">17291280</pub-id></element-citation></ref><ref id="R48"><label>48</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Negishi</surname><given-names>H</given-names></name><name><surname>Yanai</surname><given-names>H</given-names></name><name><surname>Nakajima</surname><given-names>A</given-names></name><name><surname>Koshiba</surname><given-names>R</given-names></name><name><surname>Atarashi</surname><given-names>K</given-names></name><etal></etal></person-group><article-title>Cross-interference of RLR and TLR signaling pathways modulates antibacterial T cell responses</article-title><source>Nat Immunol</source><year>2012</year><volume>13</volume><fpage>659</fpage><lpage>666</lpage><pub-id pub-id-type="pmid">22610141</pub-id></element-citation></ref><ref id="R49"><label>49</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Malley</surname><given-names>R</given-names></name><name><surname>Henneke</surname><given-names>P</given-names></name><name><surname>Morse</surname><given-names>SC</given-names></name><name><surname>Cieslewicz</surname><given-names>MJ</given-names></name><name><surname>Lipsitch</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Recognition of pneumolysin by Toll-like receptor 4 confers resistance to pneumococcal infection</article-title><source>Proc Natl Acad Sci U S A</source><year>2003</year><volume>100</volume><fpage>1966</fpage><lpage>1971</lpage><pub-id pub-id-type="pmid">12569171</pub-id></element-citation></ref><ref id="R50"><label>50</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Karlström</surname><given-names>A</given-names></name><name><surname>Heston</surname><given-names>SM</given-names></name><name><surname>Boyd</surname><given-names>KL</given-names></name><name><surname>Tuomanen</surname><given-names>EI</given-names></name><name><surname>McCullers</surname><given-names>JA</given-names></name></person-group><article-title>Toll-like receptor 2 mediates fatal immunopathology in mice during treatment of secondary pneumococcal pneumonia following influenza</article-title><source>J Infect Dis</source><year>2011</year><volume>204</volume><fpage>1358</fpage><lpage>1366</lpage><pub-id pub-id-type="pmid">21900488</pub-id></element-citation></ref><ref id="R51"><label>51</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Waterer</surname><given-names>GW</given-names></name><name><surname>Somes</surname><given-names>GW</given-names></name><name><surname>Wunderink</surname><given-names>RG</given-names></name></person-group><article-title>Monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia</article-title><source>Arch Intern Med</source><year>2001</year><volume>161</volume><fpage>1837</fpage><lpage>1842</lpage><pub-id pub-id-type="pmid">11493124</pub-id></element-citation></ref><ref id="R52"><label>52</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Watkins</surname><given-names>RR</given-names></name><name><surname>Lemonovich</surname><given-names>TL</given-names></name></person-group><article-title>Diagnosis and management of community-acquired pneumonia in adults</article-title><source>Am Fam Physician</source><year>2011</year><volume>83</volume><fpage>1299</fpage><lpage>1306</lpage><pub-id pub-id-type="pmid">21661712</pub-id></element-citation></ref><ref id="R53"><label>53</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Majhi</surname><given-names>A</given-names></name><name><surname>Adhikary</surname><given-names>R</given-names></name><name><surname>Bhattacharyya</surname><given-names>A</given-names></name><name><surname>Mahanti</surname><given-names>S</given-names></name><name><surname>Bishayi</surname><given-names>B</given-names></name></person-group><article-title>Levofloxacin-ceftriaxone combination attenuates lung inflammation in a mouse model of bacteremic pneumonia caused by multidrug-resistant <italic>Streptococcus pneumoniae</italic> via inhibition of cytolytic activities of pneumolysin and autolysin</article-title><source>Antimicrob Agents Chemother</source><year>2014</year><volume>58</volume><fpage>5164</fpage><lpage>5180</lpage><pub-id pub-id-type="pmid">24957840</pub-id></element-citation></ref><ref id="R54"><label>54</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Karlström</surname><given-names>A</given-names></name><name><surname>Boyd</surname><given-names>KL</given-names></name><name><surname>English</surname><given-names>BK</given-names></name><name><surname>McCullers</surname><given-names>JA</given-names></name></person-group><article-title>Treatment with protein synthesis inhibitors improves outcomes of secondary bacterial pneumonia after influenza</article-title><source>J Infect Dis</source><year>2009</year><volume>199</volume><fpage>311</fpage><lpage>319</lpage><pub-id pub-id-type="pmid">19113989</pub-id></element-citation></ref><ref id="R55"><label>55</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Majhi</surname><given-names>A</given-names></name><name><surname>Kundu</surname><given-names>K</given-names></name><name><surname>Adhikary</surname><given-names>R</given-names></name><name><surname>Banerjee</surname><given-names>M</given-names></name><name><surname>Mahanti</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>Combination therapy with ampicillin and azithromycin in an experimental pneumococcal pneumonia is bactericidal and effective in down regulating inflammation in mice</article-title><source>J Inflamm (Lond)</source><year>2014</year><volume>11</volume><fpage>5</fpage><pub-id pub-id-type="pmid">24565171</pub-id></element-citation></ref><ref id="R56"><label>56</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Luxameechanporn</surname><given-names>T</given-names></name><name><surname>Blair</surname><given-names>C</given-names></name><name><surname>Kirtsreesakul</surname><given-names>V</given-names></name><name><surname>Thompson</surname><given-names>K</given-names></name><name><surname>Naclerio</surname><given-names>RM</given-names></name><etal></etal></person-group><article-title>The effect of treatment with moxifloxacin or azithromycin on acute bacterial rhinosinusitis in mice</article-title><source>Int J Infect Dis</source><year>2006</year><volume>10</volume><fpage>401</fpage><lpage>406</lpage><pub-id pub-id-type="pmid">16564192</pub-id></element-citation></ref><ref id="R57"><label>57</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Goldstein</surname><given-names>LH</given-names></name><name><surname>Gabin</surname><given-names>A</given-names></name><name><surname>Fawaz</surname><given-names>A</given-names></name><name><surname>Freedberg</surname><given-names>NA</given-names></name><name><surname>Schwartz</surname><given-names>N</given-names></name><etal></etal></person-group><article-title>Azithromycin is not associated with QT prolongation in hospitalized patients with community-acquired pneumonia</article-title><source>Pharmacoepidemiol Drug Saf</source><year>2015</year><volume>24</volume><fpage>1042</fpage><lpage>1048</lpage><pub-id pub-id-type="pmid">26238864</pub-id></element-citation></ref><ref id="R58"><label>58</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Li</surname><given-names>C</given-names></name><name><surname>Yang</surname><given-names>P</given-names></name><name><surname>Zhang</surname><given-names>Y</given-names></name><name><surname>Sun</surname><given-names>Y</given-names></name><name><surname>Wang</surname><given-names>W</given-names></name><etal></etal></person-group><article-title>Corticosteroid treatment ameliorates acute lung injury induced by 2009 swine origin influenza A (H1N1) virus in mice</article-title><source>PLoS One</source><year>2012</year><volume>7</volume><fpage>e44110</fpage><pub-id pub-id-type="pmid">22952892</pub-id></element-citation></ref><ref id="R59"><label>59</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ke</surname><given-names>Han</given-names></name><name><surname>Ma</surname><given-names>Huilai</given-names></name><name><surname>An</surname><given-names>Xiangdong</given-names></name><name><surname>Su</surname><given-names>Yang</given-names></name><name><surname>Chen</surname><given-names>Jing</given-names></name><etal></etal></person-group><article-title>Early use of glucocorticoids was a risk factor for critical disease and death from pH1N1 infection</article-title><source>Clin Infect Dis</source><year>2011</year><volume>53</volume><fpage>326</fpage><lpage>333</lpage><pub-id pub-id-type="pmid">21810744</pub-id></element-citation></ref><ref id="R60"><label>60</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mifsud</surname><given-names>EJ</given-names></name><name><surname>Tan</surname><given-names>AC</given-names></name><name><surname>Short</surname><given-names>KR</given-names></name><name><surname>Brown</surname><given-names>LE</given-names></name><name><surname>Chua</surname><given-names>BY</given-names></name><etal></etal></person-group><article-title>Reducing the impact of influenza-associated secondary pneumococcal infections</article-title><source>Immunol Cell Biol</source><year>2016</year><volume>94</volume><fpage>101</fpage><lpage>108</lpage><pub-id pub-id-type="pmid">26134269</pub-id></element-citation></ref><ref id="R61"><label>61</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Reppe</surname><given-names>K</given-names></name><name><surname>Radünzel</surname><given-names>P</given-names></name><name><surname>Dietert</surname><given-names>K</given-names></name><name><surname>Tschernig</surname><given-names>T</given-names></name><name><surname>Wolff</surname><given-names>T</given-names></name><etal></etal></person-group><article-title>Pulmonary immunostimulation with MALP-2 in influenza virus-infected mice increases survival after pneumococcal superinfection</article-title><source>Infect Immun</source><year>2015</year><volume>83</volume><fpage>4617</fpage><lpage>4629</lpage><pub-id pub-id-type="pmid">26371127</pub-id></element-citation></ref><ref id="R62"><label>62</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Porte</surname><given-names>R</given-names></name><name><surname>Fougeron</surname><given-names>D</given-names></name><name><surname>Muñoz-Wolf</surname><given-names>N</given-names></name><name><surname>Tabareau</surname><given-names>J</given-names></name><name><surname>Georgel</surname><given-names>AF</given-names></name><etal></etal></person-group><article-title>A Toll-Like Receptor 5 Agonist Improves the Efficacy of Antibiotics in Treatment of Primary and Influenza Virus-Associated pneumococcal Mouse Infections</article-title><source>Antimicrob Agents Chemother</source><year>2015</year><volume>59</volume><fpage>6064</fpage><lpage>6072</lpage><pub-id pub-id-type="pmid">26195519</pub-id></element-citation></ref><ref id="R63"><label>63</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tanaka</surname><given-names>A</given-names></name><name><surname>Nakamura</surname><given-names>S</given-names></name><name><surname>Seki</surname><given-names>M</given-names></name><name><surname>Fukudome</surname><given-names>K</given-names></name><name><surname>Iwanaga</surname><given-names>N</given-names></name><etal></etal></person-group><article-title>Toll-like receptor 4 agonistic antibody promotes innate immunity against severe pneumonia induced by coinfection with influenza virus and Streptococcus pneumoniae</article-title><source>Clin Vaccine Immunol</source><year>2013</year><volume>20</volume><fpage>977</fpage><lpage>985</lpage><pub-id pub-id-type="pmid">23637040</pub-id></element-citation></ref><ref id="R64"><label>64</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chen</surname><given-names>L</given-names></name><name><surname>Guo</surname><given-names>S</given-names></name><name><surname>Wu</surname><given-names>L</given-names></name><name><surname>Hao</surname><given-names>C</given-names></name><name><surname>Xu</surname><given-names>W</given-names></name><etal></etal></person-group><article-title>Effects of recombinant IL-17F intranasal inoculation against <italic>Streptococcus pneumoniae</italic> infection in a murine model</article-title><source>Biotechnol Appl Biochem</source><year>2015</year><volume>62</volume><fpage>393</fpage><lpage>400</lpage><pub-id pub-id-type="pmid">25196250</pub-id></element-citation></ref><ref id="R65"><label>65</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Onishi</surname><given-names>M</given-names></name><name><surname>Kitano</surname><given-names>M</given-names></name><name><surname>Taniguchi</surname><given-names>K</given-names></name><name><surname>Homma</surname><given-names>T</given-names></name><name><surname>Kobayashi</surname><given-names>M</given-names></name><etal></etal></person-group><article-title>Intravenous peramivir inhibits viral replication, and leads to bacterial clearance and prevention of mortality during murine bacterial co-infection caused by influenza A(H1N1)pdm09 virus and <italic>Streptococcus pneumoniae</italic></article-title><source>Antiviral Res</source><year>2015</year><volume>117</volume><fpage>52</fpage><lpage>59</lpage><pub-id pub-id-type="pmid">25752738</pub-id></element-citation></ref><ref id="R66"><label>66</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Walther</surname><given-names>E</given-names></name><name><surname>Richter</surname><given-names>M</given-names></name><name><surname>Xu</surname><given-names>Z</given-names></name><name><surname>Kramer</surname><given-names>C</given-names></name><name><surname>von Grafenstein</surname><given-names>S</given-names></name><etal></etal></person-group><article-title>Antipneumococcal activity of neuraminidase inhibiting artocarpin</article-title><source>Int J Med Microbiol</source><year>2015</year><volume>305</volume><fpage>289</fpage><lpage>297</lpage><pub-id pub-id-type="pmid">25592264</pub-id></element-citation></ref><ref id="R67"><label>67</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Armstrong</surname><given-names>SM</given-names></name><name><surname>Mubareka</surname><given-names>S</given-names></name><name><surname>Lee</surname><given-names>WL</given-names></name></person-group><article-title>The lung microvascular endothelium as a therapeutic target in severe influenza</article-title><source>Antiviral Res</source><year>2013</year><volume>99</volume><fpage>113</fpage><lpage>118</lpage><pub-id pub-id-type="pmid">23685311</pub-id></element-citation></ref><ref id="R68"><label>68</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mathieu</surname><given-names>C</given-names></name><name><surname>Rioux</surname><given-names>G</given-names></name><name><surname>Dumas</surname><given-names>MC</given-names></name><name><surname>Leclerc</surname><given-names>D</given-names></name></person-group><article-title>Induction of innate immunity in lungs with virus-like nanoparticles leads to protection against influenza and <italic>Streptococcus pneumoniae</italic> challenge</article-title><source>Nanomedicine</source><year>2013</year><volume>9</volume><fpage>839</fpage><lpage>848</lpage><pub-id pub-id-type="pmid">23499666</pub-id></element-citation></ref><ref id="R69"><label>69</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Metzger</surname><given-names>DW</given-names></name><name><surname>Furuya</surname><given-names>Y</given-names></name><name><surname>Salmon</surname><given-names>SL</given-names></name><name><surname>Roberts</surname><given-names>S</given-names></name><name><surname>Sun</surname><given-names>K</given-names></name></person-group><article-title>Limited Efficacy of Antibacterial Vaccination Against Secondary Serotype 3 pneumococcal Pneumonia Following Influenza Infection</article-title><source>J Infect Dis</source><year>2015</year><volume>212</volume><fpage>445</fpage><lpage>452</lpage><pub-id pub-id-type="pmid">25649173</pub-id></element-citation></ref><ref id="R70"><label>70</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Klugman</surname><given-names>KP</given-names></name><name><surname>Chien</surname><given-names>YW</given-names></name><name><surname>Madhi</surname><given-names>SA</given-names></name></person-group><article-title>pneumococcal pneumonia and influenza: a deadly combination</article-title><source>Vaccine</source><year>2009</year><volume>27</volume><fpage>C9</fpage><lpage>C14</lpage><pub-id pub-id-type="pmid">19683658</pub-id></element-citation></ref></ref-list></back><floats-group><fig id="F1" orientation="portrait" position="float"><label>Figure 1</label><caption><title>Neutrophils are key players in co-infection pathogenesis</title><p id="P18">(A) Influenza damages airway epithelium and exposes receptors priming for bacterial adherence; <italic>S. pneumoniae</italic> adheres to damaged epithelium and is able to migrate through pulmonary epithelium. (B) Sentinel cells detect pathogens and damaged cells and recruit neutrophils through a chemotactic gradient for phagocytosis and bacterial killing; Neutrophils contribute to immunopathology through a variety of mechanisms as illustrated. (C) Worsened epithelial and endothelial damage due to coinfection results in bacteremia.</p></caption><graphic xlink:href="nihms784378f1"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/H2N2V1/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000C67 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 000C67 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= H2N2V1
|flux= Pmc
|étape= Corpus
|type= RBID
|clé= PMC:5154682
|texte= Lethal Synergism between Influenza and Streptococcus pneumoniae
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/RBID.i -Sk "pubmed:27981251" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd \
| NlmPubMed2Wicri -a H2N2V1
| This area was generated with Dilib version V0.6.33. |  |