1918 pandemic influenza virus and Streptococcus pneumoniae co‐infection results in activation of coagulation and widespread pulmonary thrombosis in mice and humans
Identifieur interne : 000488 ( Istex/Corpus ); précédent : 000487; suivant : 0004891918 pandemic influenza virus and Streptococcus pneumoniae co‐infection results in activation of coagulation and widespread pulmonary thrombosis in mice and humans
Auteurs : Kathie-Anne Walters ; Felice D'Agnillo ; Zong-Mei Sheng ; Jason Kindrachuk ; Louis M. Schwartzman ; Rolf E. Kuestner ; Daniel S. Chertow ; Basil T. Golding ; Jeffery K. Taubenberger ; John C. KashSource :
- The Journal of Pathology [ 0022-3417 ] ; 2016-01.
Abstract
To study bacterial co‐infection following 1918 H1N1 influenza virus infection, mice were inoculated with the 1918 influenza virus, followed by Streptococcus pneumoniae (SP) 72 h later. Co‐infected mice exhibited markedly more severe disease, shortened survival time and more severe lung pathology, including widespread thrombi. Transcriptional profiling revealed activation of coagulation only in co‐infected mice, consistent with the extensive thrombogenesis observed. Immunohistochemistry showed extensive expression of tissue factor (F3) and prominent deposition of neutrophil elastase on endothelial and epithelial cells in co‐infected mice. Lung sections of SP‐positive 1918 autopsy cases showed extensive thrombi and prominent staining for F3 in alveolar macrophages, monocytes, neutrophils, endothelial and epithelial cells, in contrast to co‐infection‐positive 2009 pandemic H1N1 autopsy cases. This study reveals that a distinctive feature of 1918 influenza virus and SP co‐infection in mice and humans is extensive expression of tissue factor and activation of the extrinsic coagulation pathway leading to widespread pulmonary thrombosis. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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DOI: 10.1002/path.4638
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Kash</name><affiliation><mods:affiliation>Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), MD, 20892, NIH, Bethesda, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: taubenbergerj@niaid.nih.gov</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">The Journal of Pathology</title><title level="j" type="alt">THE JOURNAL OF PATHOLOGY</title><idno type="ISSN">0022-3417</idno><idno type="eISSN">1096-9896</idno><imprint><biblScope unit="vol">238</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="85">85</biblScope><biblScope unit="page" to="97">97</biblScope><biblScope unit="page-count">13</biblScope><publisher>John Wiley & Sons, Ltd</publisher><pubPlace>Chichester, UK</pubPlace><date type="published" when="2016-01">2016-01</date></imprint><idno type="ISSN">0022-3417</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0022-3417</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">To study bacterial co‐infection following 1918 H1N1 influenza virus infection, mice were inoculated with the 1918 influenza virus, followed by Streptococcus pneumoniae (SP) 72 h later. Co‐infected mice exhibited markedly more severe disease, shortened survival time and more severe lung pathology, including widespread thrombi. Transcriptional profiling revealed activation of coagulation only in co‐infected mice, consistent with the extensive thrombogenesis observed. Immunohistochemistry showed extensive expression of tissue factor (F3) and prominent deposition of neutrophil elastase on endothelial and epithelial cells in co‐infected mice. Lung sections of SP‐positive 1918 autopsy cases showed extensive thrombi and prominent staining for F3 in alveolar macrophages, monocytes, neutrophils, endothelial and epithelial cells, in contrast to co‐infection‐positive 2009 pandemic H1N1 autopsy cases. This study reveals that a distinctive feature of 1918 influenza virus and SP co‐infection in mice and humans is extensive expression of tissue factor and activation of the extrinsic coagulation pathway leading to widespread pulmonary thrombosis. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Kathie‐Anne Walters</name><affiliations><json:string>Institute for Systems Biology, WA, Seattle, USA</json:string></affiliations></json:item><json:item><name>Felice D'Agnillo</name><affiliations><json:string>Laboratory of Biochemistry and Vascular Biology, Division of Hematology Research and Review, Center for Biologics Evaluation and Research, Office of Blood Research and Review, Food and Drug Administration, MD, Silver Spring, USA</json:string></affiliations></json:item><json:item><name>Zong‐Mei Sheng</name><affiliations><json:string>Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), MD, 20892, NIH, Bethesda, USA</json:string></affiliations></json:item><json:item><name>Jason Kindrachuk</name><affiliations><json:string>Critical Care Medicine Department, National Institutes of Health (NIH), MD, Bethesda, USA</json:string></affiliations></json:item><json:item><name>Louis M Schwartzman</name><affiliations><json:string>Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), MD, 20892, NIH, Bethesda, USA</json:string></affiliations></json:item><json:item><name>Rolf E Kuestner</name><affiliations><json:string>Institute for Systems Biology, WA, Seattle, USA</json:string></affiliations></json:item><json:item><name>Daniel S Chertow</name><affiliations><json:string>Critical Care Medicine Department, National Institutes of Health (NIH), Bethesda, MD, USA</json:string><json:string>Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), MD, 20892, NIH, Bethesda, USA</json:string></affiliations></json:item><json:item><name>Basil T Golding</name><affiliations><json:string>Laboratory of Biochemistry and Vascular Biology, Division of Hematology Research and Review, Center for Biologics Evaluation and Research, Office of Blood Research and Review, Food and Drug Administration, MD, Silver Spring, USA</json:string></affiliations></json:item><json:item><name>Jeffery K Taubenberger</name><affiliations><json:string>Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), MD, 20892, NIH, Bethesda, USA</json:string><json:string>E-mail: taubenbergerj@niaid.nih.gov</json:string></affiliations></json:item><json:item><name>John C Kash</name><affiliations><json:string>Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), MD, 20892, NIH, Bethesda, USA</json:string><json:string>E-mail: taubenbergerj@niaid.nih.gov</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>1918 influenza</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Streptococcus pneumoniae</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>co‐infection</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>inflammation</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>extrinsic pathway of coagulation</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>pulmonary thrombosis</value></json:item></subject><articleId><json:string>PATH4638</json:string></articleId><arkIstex>ark:/67375/WNG-W642W3HK-K</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><abstract>To study bacterial co‐infection following 1918 H1N1 influenza virus infection, mice were inoculated with the 1918 influenza virus, followed by Streptococcus pneumoniae (SP) 72 h later. Co‐infected mice exhibited markedly more severe disease, shortened survival time and more severe lung pathology, including widespread thrombi. Transcriptional profiling revealed activation of coagulation only in co‐infected mice, consistent with the extensive thrombogenesis observed. Immunohistochemistry showed extensive expression of tissue factor (F3) and prominent deposition of neutrophil elastase on endothelial and epithelial cells in co‐infected mice. Lung sections of SP‐positive 1918 autopsy cases showed extensive thrombi and prominent staining for F3 in alveolar macrophages, monocytes, neutrophils, endothelial and epithelial cells, in contrast to co‐infection‐positive 2009 pandemic H1N1 autopsy cases. This study reveals that a distinctive feature of 1918 influenza virus and SP co‐infection in mice and humans is extensive expression of tissue factor and activation of the extrinsic coagulation pathway leading to widespread pulmonary thrombosis. Copyright © 2015 Pathological Society of Great Britain and Ireland. 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<ref target="http://www.tei-c.org/">We use TEI</ref></desc></application></appInfo></encodingDesc><profileDesc><abstract style="main" xml:id="path4638-abs-0001"><head>Abstract</head><p xml:id="path4638-para-0001">To study bacterial co‐infection following 1918 <hi rend="fc">H1N1</hi> influenza virus infection, mice were inoculated with the 1918 influenza virus, followed by <hi rend="fi">Streptococcus pneumoniae</hi> (<hi rend="fc">SP</hi>) 72 h later. Co‐infected mice exhibited markedly more severe disease, shortened survival time and more severe lung pathology, including widespread thrombi. Transcriptional profiling revealed activation of coagulation only in co‐infected mice, consistent with the extensive thrombogenesis observed. Immunohistochemistry showed extensive expression of tissue factor (<hi rend="fc">F3</hi>) and prominent deposition of neutrophil elastase on endothelial and epithelial cells in co‐infected mice. Lung sections of <hi rend="fc">SP</hi>‐positive 1918 autopsy cases showed extensive thrombi and prominent staining for <hi rend="fc">F3</hi> in alveolar macrophages, monocytes, neutrophils, endothelial and epithelial cells, in contrast to co‐infection‐positive 2009 pandemic <hi rend="fc">H1N1</hi> autopsy cases. This study reveals that a distinctive feature of 1918 influenza virus and <hi rend="fc">SP</hi> co‐infection in mice and humans is extensive expression of tissue factor and activation of the extrinsic coagulation pathway leading to widespread pulmonary thrombosis. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</p></abstract><textClass><keywords><term xml:id="path4638-kwd-0001">1918 influenza</term><term xml:id="path4638-kwd-0002"><hi rend="fi">Streptococcus pneumoniae</hi></term><term xml:id="path4638-kwd-0003">co‐infection</term><term xml:id="path4638-kwd-0004">inflammation</term><term xml:id="path4638-kwd-0005">extrinsic pathway of coagulation</term><term xml:id="path4638-kwd-0006">pulmonary thrombosis</term></keywords><keywords rend="articleCategory"><term>Original Paper</term></keywords><keywords rend="tocHeading1"><term>Original Papers</term></keywords></textClass><langUsage><language ident="en"></language></langUsage></profileDesc><revisionDesc><change when="2019-12-20" who="#istex" xml:id="pub2tei">formatting</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/WNG-W642W3HK-K/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en" xml:id="path4638"><header><publicationMeta level="product"><publisherInfo><publisherName>John Wiley & Sons, Ltd</publisherName><publisherLoc>Chichester, UK</publisherLoc></publisherInfo>
<doi>10.1002/(ISSN)1096-9896</doi><issn type="print">0022-3417</issn><issn type="electronic">1096-9896</issn><idGroup><id type="product" value="PATH"></id></idGroup><titleGroup><title type="main" sort="THE JOURNAL OF PATHOLOGY">The Journal of Pathology</title><title type="short">J. Pathol.</title></titleGroup></publicationMeta><publicationMeta level="part" position="10"><doi origin="wiley">10.1002/path.2016.238.issue-1</doi><copyright ownership="thirdParty">Copyright © 2016 Pathological Society of Great Britain and Ireland</copyright><numberingGroup><numbering type="journalVolume" number="238">238</numbering><numbering type="journalIssue">1</numbering></numberingGroup><coverDate startDate="2016-01">January 2016</coverDate></publicationMeta><publicationMeta level="unit" position="120" type="article" status="forIssue"><doi>10.1002/path.4638</doi><idGroup><id type="unit" value="PATH4638"></id></idGroup><countGroup><count type="pageTotal" number="13"></count></countGroup><titleGroup><title type="articleCategory">Original Paper</title><title type="tocHeading1">Original Papers</title></titleGroup><copyright ownership="publisher">Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</copyright><eventGroup><event type="manuscriptReceived" date="2015-07-23"></event><event type="manuscriptRevised" date="2015-08-25"></event><event type="manuscriptAccepted" date="2015-09-07"></event><event type="xmlCreated" agent="Laserwords Private Ltd." date="2015-09-28"></event><event type="publishedOnlineAccepted" date="2015-09-18"></event><event type="publishedOnlineEarlyUnpaginated" date="2015-10-14"></event><event type="firstOnline" date="2015-10-14"></event><event type="publishedOnlineFinalForm" date="2015-12-16"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:5.0.6 mode:FullText" date="2017-02-09"></event></eventGroup><numberingGroup><numbering type="pageFirst">85</numbering><numbering type="pageLast">97</numbering></numberingGroup><correspondenceTo><i>Correspondence to</i>: JK Taubenberger and JC Kash, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), 33 North Drive, MSC 3203, Bethesda, MD 20892, USA. E‐mail: <email>taubenbergerj@niaid.nih.gov</email> and <email>kashj@niaid.nih.gov</email></correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:PATH.PATH4638.pdf"></link></linkGroup></publicationMeta><contentMeta><titleGroup><title type="main">1918 pandemic influenza virus and <fi>Streptococcus pneumoniae</fi> co‐infection results in activation of coagulation and widespread pulmonary thrombosis in mice and humans</title><title type="short">1918 influenza and pneumococcus co‐infection causes pulmonary thrombosis</title><title type="shortAuthors">KA Walters <fi>et al</fi></title></titleGroup><creators><creator creatorRole="author" xml:id="path4638-cr-0001" affiliationRef="#path4638-aff-0001"><personName><givenNames>Kathie‐Anne</givenNames>
<familyName>Walters</familyName></personName></creator><creator creatorRole="author" xml:id="path4638-cr-0002" affiliationRef="#path4638-aff-0002"><personName><givenNames>Felice</givenNames>
<familyName>D'Agnillo</familyName></personName></creator><creator creatorRole="author" xml:id="path4638-cr-0003" affiliationRef="#path4638-aff-0004"><personName><givenNames>Zong‐Mei</givenNames>
<familyName>Sheng</familyName></personName></creator><creator creatorRole="author" xml:id="path4638-cr-0004" affiliationRef="#path4638-aff-0003"><personName><givenNames>Jason</givenNames>
<familyName>Kindrachuk</familyName></personName></creator><creator creatorRole="author" xml:id="path4638-cr-0005" affiliationRef="#path4638-aff-0004"><personName><givenNames>Louis M</givenNames>
<familyName>Schwartzman</familyName></personName></creator><creator creatorRole="author" xml:id="path4638-cr-0006" affiliationRef="#path4638-aff-0001"><personName><givenNames>Rolf E</givenNames>
<familyName>Kuestner</familyName></personName></creator><creator creatorRole="author" xml:id="path4638-cr-0007" affiliationRef="#path4638-aff-0003 #path4638-aff-0004"><personName><givenNames>Daniel S</givenNames>
<familyName>Chertow</familyName></personName></creator><creator creatorRole="author" xml:id="path4638-cr-0008" affiliationRef="#path4638-aff-0002"><personName><givenNames>Basil T</givenNames>
<familyName>Golding</familyName></personName></creator><creator creatorRole="author" xml:id="path4638-cr-0009" affiliationRef="#path4638-aff-0004" corresponding="yes"><personName><givenNames>Jeffery K</givenNames>
<familyName>Taubenberger</familyName></personName></creator><creator creatorRole="author" xml:id="path4638-cr-0010" affiliationRef="#path4638-aff-0004" corresponding="yes"><personName><givenNames>John C</givenNames>
<familyName>Kash</familyName></personName></creator></creators><affiliationGroup xml:id="path4638-affgp-0001"><affiliation countryCode="US" type="organization" xml:id="path4638-aff-0001"><orgName>Institute for Systems Biology</orgName><address><city>Seattle</city><countryPart>WA</countryPart><country>USA</country></address></affiliation><affiliation countryCode="US" type="organization" xml:id="path4638-aff-0002"><orgDiv>Laboratory of Biochemistry and Vascular Biology, Division of Hematology Research and Review, Center for Biologics Evaluation and Research, Office of Blood Research and Review</orgDiv><orgName>Food and Drug Administration</orgName><address><city>Silver Spring</city><countryPart>MD</countryPart><country>USA</country></address></affiliation><affiliation countryCode="US" type="organization" xml:id="path4638-aff-0003"><orgDiv>Critical Care Medicine Department</orgDiv><orgName>National Institutes of Health (NIH)</orgName><address><city>Bethesda</city><countryPart>MD</countryPart><country>USA</country></address></affiliation><affiliation countryCode="US" type="organization" xml:id="path4638-aff-0004"><orgDiv>Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases</orgDiv><orgName>National Institute of Allergy and Infectious Diseases (NIAID)</orgName><address><city>NIH, Bethesda</city><countryPart>MD</countryPart><postCode>20892</postCode><country>USA</country></address></affiliation></affiliationGroup><keywordGroup type="author"><keyword xml:id="path4638-kwd-0001">1918 influenza</keyword><keyword xml:id="path4638-kwd-0002"><fi>Streptococcus pneumoniae</fi></keyword><keyword xml:id="path4638-kwd-0003">co‐infection</keyword><keyword xml:id="path4638-kwd-0004">inflammation</keyword><keyword xml:id="path4638-kwd-0005">extrinsic pathway of coagulation</keyword><keyword xml:id="path4638-kwd-0006">pulmonary thrombosis</keyword></keywordGroup><fundingInfo><fundingAgency fundRefName="National Institutes of Health" funderDoi="10.13039/100000002">National Institutes of Health (NIH)</fundingAgency></fundingInfo><fundingInfo><fundingAgency fundRefName="National Institute of Allergy and Infectious Diseases" funderDoi="10.13039/100000060">National Institute of Allergy and Infectious Diseases (NIAID)</fundingAgency></fundingInfo><supportingInformation xml:id="path4638-supinf-0001"><supportingInfoItem xml:id="path4638-supitem-0001"><mediaResource alt="supplementary data" mimeType="application/msword" rendition="webOriginal" href="urn-x:wiley:00223417:media:path4638:path4638-sup-0001-AppendixS1"></mediaResource><caption><b>Supplementary materials and methods.</b></caption></supportingInfoItem><supportingInfoItem xml:id="path4638-supitem-0002"><mediaResource alt="supplementary data" mimeType="image/tiff" rendition="webOriginal" href="urn-x:wiley:00223417:media:path4638:path4638-sup-0002-FigureS1"></mediaResource><caption><b>Figure S1.</b> Detection of <fi>16S</fi> rRNA in spleen in SP‐alone and 1918 co‐infected mice. Quantification of bacterial <fi>16S</fi> rRNA present in spleen tissue, using qRT–PCR analysis. Data are presented as mean ± SE of 2<sup><fi>–ΔΔC</fi><sc>t</sc></sup> values relative to <fi>Gapdh</fi> present in RNA isolated from the lungs of three mice/group</caption></supportingInfoItem><supportingInfoItem xml:id="path4638-supitem-0003"><mediaResource alt="supplementary data" mimeType="image/tiff" rendition="webOriginal" href="urn-x:wiley:00223417:media:path4638:path4638-sup-0003-FigureS2"></mediaResource><caption><b>Figure S2.</b> Host transcriptional response in the lungs of mice inoculated with influenza virus and SP. Expression profiles of 14 800 sequences that were regulated (two‐fold, <fi>p <</fi> 0.01) in at least one experimental condition. Each column represents gene expression data from an individual experiment comparing lung tissue from an infected animal relative to pooled tissue from mock mice (<fi>n =</fi> 9). Genes shown in red were increased, genes shown in green decreased and genes in black indicate no change in expression in infected relative to uninfected mice</caption></supportingInfoItem><supportingInfoItem xml:id="path4638-supitem-0004"><mediaResource alt="supplementary data" mimeType="image/tiff" rendition="webOriginal" href="urn-x:wiley:00223417:media:path4638:path4638-sup-0004-FigureS3"></mediaResource><caption><b>Figure S3.</b> Inflammatory gene expression in the lungs of mice inoculated with 1918 influenza virus and SP. Expression profiles of inflammation‐related genes that were regulated (two‐fold, <fi>p <</fi> 0.01) in at least one experimental condition. Each column represents gene expression data from an individual experiment comparing lung tissue from an infected animal relative to pooled tissue from mock mice (<fi>n =</fi> 9). Genes shown in red were increased, genes shown in green decreased and genes in black indicate no change in expression in infected relative to uninfected mice</caption></supportingInfoItem><supportingInfoItem xml:id="path4638-supitem-0005"><mediaResource alt="supplementary data" mimeType="image/tiff" rendition="webOriginal" href="urn-x:wiley:00223417:media:path4638:path4638-sup-0005-FigureS4"></mediaResource><caption><b>Figure S4.</b> 1918 and SP co‐infection induces extensive tissue plasminogen activator expression. Mouse lung sections harvested at 6 days post‐infection with influenza virus (3 days post‐infection with SP in co‐infection groups) were stained for tissue plasminogen activator (PLAT). (A) 1918 alone and (C) SP alone showed similar PLAT expression levels. (B) 1918‐SP‐infected mice showed extensive cell‐associated and extracellular PLAT immunoreactivity in regions with inflammation and damage; (inset) increased PLAT expression was associated with infiltrates and alveolar vessels in 1918‐SP‐infected mice. Original magnifications = (A–C) × 40; (insets) × 600</caption></supportingInfoItem><supportingInfoItem xml:id="path4638-supitem-0006"><mediaResource alt="supplementary data" mimeType="image/tiff" rendition="webOriginal" href="urn-x:wiley:00223417:media:path4638:path4638-sup-0006-FigureS5"></mediaResource><caption><b>Figure S5.</b> Time course of Ly6G staining in lungs of mice infected with 1918 influenza virus alone, SP alone or co‐infected with 1918 influenza and SP. Mouse lung sections harvested at days 4–6 post‐1918 (days +1 to +3 post‐SP) were stained for neutrophil Ly6G using the 1A8 monoclonal antibody; original magnification = ×100</caption></supportingInfoItem><supportingInfoItem xml:id="path4638-supitem-0007"><mediaResource alt="supplementary data" mimeType="image/tiff" rendition="webOriginal" href="urn-x:wiley:00223417:media:path4638:path4638-sup-0007-FigureS6"></mediaResource><caption><b>Figure S6.</b> Time course of myeloperoxidase (MPO) staining in lungs of mice infected with 1918 influenza virus alone, SP alone or co‐infected with 1918 influenza and SP. Mouse lung sections harvested at days 4–6 post‐1918 (days +1 to +3 post‐SP) were stained for MPO; original magnification = ×100</caption></supportingInfoItem><supportingInfoItem xml:id="path4638-supitem-0008"><mediaResource alt="supplementary data" mimeType="image/tiff" rendition="webOriginal" href="urn-x:wiley:00223417:media:path4638:path4638-sup-0008-FigureS7"></mediaResource><caption><b>Figure S7.</b> Time course of ELANE staining in lungs of mice infected with 1918 influenza virus alone, SP alone or co‐infected with 1918 influenza and SP. Mouse lung sections harvested at days 4–6 post‐1918 (days +1 to +3 post‐SP) were stained for ELANE; original magnification = ×100</caption></supportingInfoItem><supportingInfoItem xml:id="path4638-supitem-0009"><mediaResource alt="supplementary data" mimeType="image/tiff" rendition="webOriginal" href="urn-x:wiley:00223417:media:path4638:path4638-sup-0009-FigureS8"></mediaResource><caption><b>Figure S8.</b> Time course of CD11b staining in lungs of mice infected with 1918 influenza virus alone, SP alone or co‐infected with 1918 influenza and SP. Mouse lung sections harvested at days 4–6 post‐1918 (days +1 to +3 post‐SP) were stained for CD11b; original magnification = ×100</caption></supportingInfoItem><supportingInfoItem xml:id="path4638-supitem-0010"><mediaResource alt="supplementary data" mimeType="image/tiff" rendition="webOriginal" href="urn-x:wiley:00223417:media:path4638:path4638-sup-0010-FigureS9"></mediaResource><caption><b>Figure S9.</b> Time course of F3 staining in lungs of mice infected with 1918 influenza virus alone, SP alone or co‐infected with 1918 influenza and SP. Mouse lung sections harvested at days 4–6 post‐1918 (days +1 to +3 post‐SP) were stained for F3; original magnification = ×100</caption></supportingInfoItem><supportingInfoItem xml:id="path4638-supitem-0011"><mediaResource alt="supplementary data" mimeType="image/tiff" rendition="webOriginal" href="urn-x:wiley:00223417:media:path4638:path4638-sup-0011-FigureS10"></mediaResource><caption><b>Figure S10.</b> Thrombin staining in lungs of mice infected with 1918 influenza virus alone, SP alone or co‐infected with 1918 influenza and SP. Mouse lung sections harvested at 6 days post‐infection with influenza virus (3 days post‐infection with SP in co‐infection groups) were stained for thrombin; original magnifications = ×100; (insets) × 600</caption></supportingInfoItem><supportingInfoItem xml:id="path4638-supitem-0012"><mediaResource alt="supplementary data" mimeType="image/tiff" rendition="webOriginal" href="urn-x:wiley:00223417:media:path4638:path4638-sup-0012-FigureS11"></mediaResource><caption><b>Figure S11.</b> Model of host responses and relationship to thrombogenesis during 1918 influenza and SP co‐infection. 1, 1918 viral infection alone causes widespread respiratory epithelial cell injury with necrotizing bronchitis, bronchiolitis and neutrophilic alveolitis, elicits an immunopathogenic inflammatory response and induces damage to airway epithelial cells, which promotes bacterial attachment and replication. 2, Inflammation, congestion and oedema increase pulmonary and venous pressure and reduce blood flow. 3, 1918 viral and bacterial pathogens individually and synergistically activate neutrophils; viral infection results in high levels of cytokine, chemokine, type I interferon (IFN) expression and death receptor activation, while bacterial infection stimulates TLR2 and other pattern recognition receptors (PRRs) on neutrophils and macrophages. 4, Prominent expression of tissue factor (F3) by neutrophils and macrophages promotes platelet activation and aggregation, leading to hypercoagulability. 5, Secretion of elastase (ELANE) by neutrophils damages vascular endothelial cells and promotes thrombus formation; ELANE also mediates damage to airway and alveolar epithelial cells. 6, Viral infection‐induced reactive oxygen species (ROS) have also been shown to cause significant oxidative damage to airway and alveolar epithelial cell and to worsen lung pathology</caption></supportingInfoItem><supportingInfoItem xml:id="path4638-supitem-0013"><mediaResource alt="supplementary data" mimeType="image/tiff" rendition="webOriginal" href="urn-x:wiley:00223417:media:path4638:path4638-sup-0013-TableS1"></mediaResource><caption><b>Table S1.</b> Primers and probes used in this study</caption></supportingInfoItem></supportingInformation><abstractGroup><abstract type="main" xml:id="path4638-abs-0001"><title type="main">Abstract</title><p xml:id="path4638-para-0001">To study bacterial co‐infection following 1918 <fc>H1N1</fc> influenza virus infection, mice were inoculated with the 1918 influenza virus, followed by <fi>Streptococcus pneumoniae</fi> (<fc>SP</fc>) 72 h later. Co‐infected mice exhibited markedly more severe disease, shortened survival time and more severe lung pathology, including widespread thrombi. Transcriptional profiling revealed activation of coagulation only in co‐infected mice, consistent with the extensive thrombogenesis observed. Immunohistochemistry showed extensive expression of tissue factor (<fc>F3</fc>) and prominent deposition of neutrophil elastase on endothelial and epithelial cells in co‐infected mice. Lung sections of <fc>SP</fc>‐positive 1918 autopsy cases showed extensive thrombi and prominent staining for <fc>F3</fc> in alveolar macrophages, monocytes, neutrophils, endothelial and epithelial cells, in contrast to co‐infection‐positive 2009 pandemic <fc>H1N1</fc> autopsy cases. This study reveals that a distinctive feature of 1918 influenza virus and <fc>SP</fc> co‐infection in mice and humans is extensive expression of tissue factor and activation of the extrinsic coagulation pathway leading to widespread pulmonary thrombosis. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</p></abstract></abstractGroup></contentMeta><noteGroup xml:id="path4638-ntgp-0001"><note xml:id="path4638-note-0001" numbered="no">No conflicts of interest were declared.</note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>1918 pandemic influenza virus and Streptococcus pneumoniae co‐infection results in activation of coagulation and widespread pulmonary thrombosis in mice and humans</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>1918 influenza and pneumococcus co‐infection causes pulmonary thrombosis</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>1918 pandemic influenza virus and Streptococcus pneumoniae co‐infection results in activation of coagulation and widespread pulmonary thrombosis in mice and humans</title></titleInfo><name type="personal"><namePart type="given">Kathie‐Anne</namePart><namePart type="family">Walters</namePart><affiliation>Institute for Systems Biology, WA, Seattle, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Felice</namePart><namePart type="family">D'Agnillo</namePart><affiliation>Laboratory of Biochemistry and Vascular Biology, Division of Hematology Research and Review, Center for Biologics Evaluation and Research, Office of Blood Research and Review, Food and Drug Administration, MD, Silver Spring, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Zong‐Mei</namePart><namePart type="family">Sheng</namePart><affiliation>Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), MD, 20892, NIH, Bethesda, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jason</namePart><namePart type="family">Kindrachuk</namePart><affiliation>Critical Care Medicine Department, National Institutes of Health (NIH), MD, Bethesda, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Louis M</namePart><namePart type="family">Schwartzman</namePart><affiliation>Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), MD, 20892, NIH, Bethesda, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Rolf E</namePart><namePart type="family">Kuestner</namePart><affiliation>Institute for Systems Biology, WA, Seattle, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Daniel S</namePart><namePart type="family">Chertow</namePart><affiliation>Critical Care Medicine Department, National Institutes of Health (NIH), Bethesda, MD, USA</affiliation><affiliation>Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), MD, 20892, NIH, Bethesda, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Basil T</namePart><namePart type="family">Golding</namePart><affiliation>Laboratory of Biochemistry and Vascular Biology, Division of Hematology Research and Review, Center for Biologics Evaluation and Research, Office of Blood Research and Review, Food and Drug Administration, MD, Silver Spring, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jeffery K</namePart><namePart type="family">Taubenberger</namePart><affiliation>Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), MD, 20892, NIH, Bethesda, USA</affiliation><affiliation>E-mail: taubenbergerj@niaid.nih.gov</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">John C</namePart><namePart type="family">Kash</namePart><affiliation>Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), MD, 20892, NIH, Bethesda, USA</affiliation><affiliation>E-mail: taubenbergerj@niaid.nih.gov</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-6N5SZHKN-D">article</genre><originInfo><publisher>John Wiley & Sons, Ltd</publisher><place><placeTerm type="text">Chichester, UK</placeTerm></place><dateIssued encoding="w3cdtf">2016-01</dateIssued><dateCreated encoding="w3cdtf">2015-09-28</dateCreated><dateCaptured encoding="w3cdtf">2015-07-23</dateCaptured><dateValid encoding="w3cdtf">2015-09-07</dateValid><copyrightDate encoding="w3cdtf">2016</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><abstract>To study bacterial co‐infection following 1918 H1N1 influenza virus infection, mice were inoculated with the 1918 influenza virus, followed by Streptococcus pneumoniae (SP) 72 h later. Co‐infected mice exhibited markedly more severe disease, shortened survival time and more severe lung pathology, including widespread thrombi. Transcriptional profiling revealed activation of coagulation only in co‐infected mice, consistent with the extensive thrombogenesis observed. Immunohistochemistry showed extensive expression of tissue factor (F3) and prominent deposition of neutrophil elastase on endothelial and epithelial cells in co‐infected mice. Lung sections of SP‐positive 1918 autopsy cases showed extensive thrombi and prominent staining for F3 in alveolar macrophages, monocytes, neutrophils, endothelial and epithelial cells, in contrast to co‐infection‐positive 2009 pandemic H1N1 autopsy cases. This study reveals that a distinctive feature of 1918 influenza virus and SP co‐infection in mice and humans is extensive expression of tissue factor and activation of the extrinsic coagulation pathway leading to widespread pulmonary thrombosis. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</abstract><note type="additional physical form">Supplementary materials and methods.Figure S1. Detection of 16S rRNA in spleen in SP‐alone and 1918 co‐infected mice. Quantification of bacterial 16S rRNA present in spleen tissue, using qRT–PCR analysis. Data are presented as mean ± SE of 2–ΔΔCt values relative to Gapdh present in RNA isolated from the lungs of three mice/groupFigure S2. Host transcriptional response in the lungs of mice inoculated with influenza virus and SP. Expression profiles of 14 800 sequences that were regulated (two‐fold, p < 0.01) in at least one experimental condition. Each column represents gene expression data from an individual experiment comparing lung tissue from an infected animal relative to pooled tissue from mock mice (n = 9). Genes shown in red were increased, genes shown in green decreased and genes in black indicate no change in expression in infected relative to uninfected miceFigure S3. Inflammatory gene expression in the lungs of mice inoculated with 1918 influenza virus and SP. Expression profiles of inflammation‐related genes that were regulated (two‐fold, p < 0.01) in at least one experimental condition. Each column represents gene expression data from an individual experiment comparing lung tissue from an infected animal relative to pooled tissue from mock mice (n = 9). Genes shown in red were increased, genes shown in green decreased and genes in black indicate no change in expression in infected relative to uninfected miceFigure S4. 1918 and SP co‐infection induces extensive tissue plasminogen activator expression. Mouse lung sections harvested at 6 days post‐infection with influenza virus (3 days post‐infection with SP in co‐infection groups) were stained for tissue plasminogen activator (PLAT). (A) 1918 alone and (C) SP alone showed similar PLAT expression levels. (B) 1918‐SP‐infected mice showed extensive cell‐associated and extracellular PLAT immunoreactivity in regions with inflammation and damage; (inset) increased PLAT expression was associated with infiltrates and alveolar vessels in 1918‐SP‐infected mice. Original magnifications = (A–C) × 40; (insets) × 600Figure S5. Time course of Ly6G staining in lungs of mice infected with 1918 influenza virus alone, SP alone or co‐infected with 1918 influenza and SP. Mouse lung sections harvested at days 4–6 post‐1918 (days +1 to +3 post‐SP) were stained for neutrophil Ly6G using the 1A8 monoclonal antibody; original magnification = ×100Figure S6. Time course of myeloperoxidase (MPO) staining in lungs of mice infected with 1918 influenza virus alone, SP alone or co‐infected with 1918 influenza and SP. Mouse lung sections harvested at days 4–6 post‐1918 (days +1 to +3 post‐SP) were stained for MPO; original magnification = ×100Figure S7. Time course of ELANE staining in lungs of mice infected with 1918 influenza virus alone, SP alone or co‐infected with 1918 influenza and SP. Mouse lung sections harvested at days 4–6 post‐1918 (days +1 to +3 post‐SP) were stained for ELANE; original magnification = ×100Figure S8. Time course of CD11b staining in lungs of mice infected with 1918 influenza virus alone, SP alone or co‐infected with 1918 influenza and SP. Mouse lung sections harvested at days 4–6 post‐1918 (days +1 to +3 post‐SP) were stained for CD11b; original magnification = ×100Figure S9. Time course of F3 staining in lungs of mice infected with 1918 influenza virus alone, SP alone or co‐infected with 1918 influenza and SP. Mouse lung sections harvested at days 4–6 post‐1918 (days +1 to +3 post‐SP) were stained for F3; original magnification = ×100Figure S10. Thrombin staining in lungs of mice infected with 1918 influenza virus alone, SP alone or co‐infected with 1918 influenza and SP. Mouse lung sections harvested at 6 days post‐infection with influenza virus (3 days post‐infection with SP in co‐infection groups) were stained for thrombin; original magnifications = ×100; (insets) × 600Figure S11. Model of host responses and relationship to thrombogenesis during 1918 influenza and SP co‐infection. 1, 1918 viral infection alone causes widespread respiratory epithelial cell injury with necrotizing bronchitis, bronchiolitis and neutrophilic alveolitis, elicits an immunopathogenic inflammatory response and induces damage to airway epithelial cells, which promotes bacterial attachment and replication. 2, Inflammation, congestion and oedema increase pulmonary and venous pressure and reduce blood flow. 3, 1918 viral and bacterial pathogens individually and synergistically activate neutrophils; viral infection results in high levels of cytokine, chemokine, type I interferon (IFN) expression and death receptor activation, while bacterial infection stimulates TLR2 and other pattern recognition receptors (PRRs) on neutrophils and macrophages. 4, Prominent expression of tissue factor (F3) by neutrophils and macrophages promotes platelet activation and aggregation, leading to hypercoagulability. 5, Secretion of elastase (ELANE) by neutrophils damages vascular endothelial cells and promotes thrombus formation; ELANE also mediates damage to airway and alveolar epithelial cells. 6, Viral infection‐induced reactive oxygen species (ROS) have also been shown to cause significant oxidative damage to airway and alveolar epithelial cell and to worsen lung pathologyTable S1. 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