Transcriptomic Analysis Reveals a Mechanism for a Prefibrotic Phenotype in STAT1 Knockout Mice during Severe Acute Respiratory Syndrome Coronavirus Infection▿ †
Identifieur interne : 000D01 ( Pmc/Corpus ); précédent : 000D00; suivant : 000D02Transcriptomic Analysis Reveals a Mechanism for a Prefibrotic Phenotype in STAT1 Knockout Mice during Severe Acute Respiratory Syndrome Coronavirus Infection▿ †
Auteurs : Gregory A. Zornetzer ; Matthew B. Frieman ; Elizabeth Rosenzweig ; Marcus J. Korth ; Carly Page ; Ralph S. Baric ; Michael G. KatzeSource :
- Journal of Virology [ 0022-538X ] ; 2010.
Abstract
Severe acute respiratory syndrome coronavirus (SARS-CoV) infection can cause the development of severe end-stage lung disease characterized by acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. The mechanisms by which pulmonary lesions and fibrosis are generated during SARS-CoV infection are not known. Using high-throughput mRNA profiling, we examined the transcriptional response of wild-type (WT), type I interferon receptor knockout (IFNAR1−/−), and STAT1 knockout (STAT1−/−) mice infected with a recombinant mouse-adapted SARS-CoV (rMA15) to better understand the contribution of specific gene expression changes to disease progression. Despite a deletion of the type I interferon receptor, strong expression of interferon-stimulated genes was observed in the lungs of IFNAR1−/− mice, contributing to clearance of the virus. In contrast, STAT1−/− mice exhibited a defect in the expression of interferon-stimulated genes and were unable to clear the infection, resulting in a lethal outcome. STAT1−/− mice exhibited dysregulation of T-cell and macrophage differentiation, leading to a TH2-biased immune response and the development of alternatively activated macrophages that mediate a profibrotic environment within the lung. We propose that a combination of impaired viral clearance and T-cell/macrophage dysregulation causes the formation of prefibrotic lesions in the lungs of rMA15-infected STAT1−/− mice.
Url:
DOI: 10.1128/JVI.01130-10
PubMed: 20702617
PubMed Central: 2953159
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Transcriptomic Analysis Reveals a Mechanism for a Prefibrotic Phenotype in STAT1 Knockout Mice during Severe Acute Respiratory Syndrome Coronavirus Infection<xref ref-type="fn" rid="fn4">▿</xref> <xref ref-type="fn" rid="fn1">†</xref> </title><author><name sortKey="Zornetzer, Gregory A" sort="Zornetzer, Gregory A" uniqKey="Zornetzer G" first="Gregory A." last="Zornetzer">Gregory A. Zornetzer</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Frieman, Matthew B" sort="Frieman, Matthew B" uniqKey="Frieman M" first="Matthew B." last="Frieman">Matthew B. Frieman</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Rosenzweig, Elizabeth" sort="Rosenzweig, Elizabeth" uniqKey="Rosenzweig E" first="Elizabeth" last="Rosenzweig">Elizabeth Rosenzweig</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Korth, Marcus J" sort="Korth, Marcus J" uniqKey="Korth M" first="Marcus J." last="Korth">Marcus J. Korth</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Page, Carly" sort="Page, Carly" uniqKey="Page C" first="Carly" last="Page">Carly Page</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Katze, Michael G" sort="Katze, Michael G" uniqKey="Katze M" first="Michael G." last="Katze">Michael G. Katze</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">20702617</idno><idno type="pmc">2953159</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2953159</idno><idno type="RBID">PMC:2953159</idno><idno type="doi">10.1128/JVI.01130-10</idno><date when="2010">2010</date><idno type="wicri:Area/Pmc/Corpus">000D01</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000D01</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Transcriptomic Analysis Reveals a Mechanism for a Prefibrotic Phenotype in STAT1 Knockout Mice during Severe Acute Respiratory Syndrome Coronavirus Infection<xref ref-type="fn" rid="fn4">▿</xref> <xref ref-type="fn" rid="fn1">†</xref> </title><author><name sortKey="Zornetzer, Gregory A" sort="Zornetzer, Gregory A" uniqKey="Zornetzer G" first="Gregory A." last="Zornetzer">Gregory A. Zornetzer</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Frieman, Matthew B" sort="Frieman, Matthew B" uniqKey="Frieman M" first="Matthew B." last="Frieman">Matthew B. Frieman</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Rosenzweig, Elizabeth" sort="Rosenzweig, Elizabeth" uniqKey="Rosenzweig E" first="Elizabeth" last="Rosenzweig">Elizabeth Rosenzweig</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Korth, Marcus J" sort="Korth, Marcus J" uniqKey="Korth M" first="Marcus J." last="Korth">Marcus J. Korth</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Page, Carly" sort="Page, Carly" uniqKey="Page C" first="Carly" last="Page">Carly Page</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Katze, Michael G" sort="Katze, Michael G" uniqKey="Katze M" first="Michael G." last="Katze">Michael G. Katze</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author></analytic><series><title level="j">Journal of Virology</title><idno type="ISSN">0022-538X</idno><idno type="eISSN">1098-5514</idno><imprint><date when="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Severe acute respiratory syndrome coronavirus (SARS-CoV) infection can cause the development of severe end-stage lung disease characterized by acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. The mechanisms by which pulmonary lesions and fibrosis are generated during SARS-CoV infection are not known. Using high-throughput mRNA profiling, we examined the transcriptional response of wild-type (WT), type I interferon receptor knockout (IFNAR1<sup>−/−</sup>), and STAT1 knockout (STAT1<sup>−/−</sup>) mice infected with a recombinant mouse-adapted SARS-CoV (rMA15) to better understand the contribution of specific gene expression changes to disease progression. Despite a deletion of the type I interferon receptor, strong expression of interferon-stimulated genes was observed in the lungs of IFNAR1<sup>−/−</sup> mice, contributing to clearance of the virus. In contrast, STAT1<sup>−/−</sup> mice exhibited a defect in the expression of interferon-stimulated genes and were unable to clear the infection, resulting in a lethal outcome. STAT1<sup>−/−</sup> mice exhibited dysregulation of T-cell and macrophage differentiation, leading to a T<sub>H</sub>2-biased immune response and the development of alternatively activated macrophages that mediate a profibrotic environment within the lung. We propose that a combination of impaired viral clearance and T-cell/macrophage dysregulation causes the formation of prefibrotic lesions in the lungs of rMA15-infected STAT1<sup>−/−</sup> mice.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Virol</journal-id><journal-id journal-id-type="publisher-id">jvirol</journal-id><journal-title-group><journal-title>Journal of Virology</journal-title></journal-title-group><issn pub-type="ppub">0022-538X</issn><issn pub-type="epub">1098-5514</issn><publisher><publisher-name>American Society for Microbiology (ASM)</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">20702617</article-id><article-id pub-id-type="pmc">2953159</article-id><article-id pub-id-type="publisher-id">1130-10</article-id><article-id pub-id-type="doi">10.1128/JVI.01130-10</article-id><article-categories><subj-group subj-group-type="heading"><subject>Pathogenesis and Immunity</subject></subj-group></article-categories><title-group><article-title>Transcriptomic Analysis Reveals a Mechanism for a Prefibrotic Phenotype in STAT1 Knockout Mice during Severe Acute Respiratory Syndrome Coronavirus Infection<xref ref-type="fn" rid="fn4">▿</xref> <xref ref-type="fn" rid="fn1">†</xref> </article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Zornetzer</surname><given-names>Gregory A.</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="fn" rid="fn3">‡</xref><xref ref-type="fn" rid="fn2">¶</xref></contrib><contrib contrib-type="author"><name><surname>Frieman</surname><given-names>Matthew B.</given-names></name><xref ref-type="aff" rid="aff1">2</xref><xref ref-type="fn" rid="fn2">‡</xref></contrib><contrib contrib-type="author"><name><surname>Rosenzweig</surname><given-names>Elizabeth</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Korth</surname><given-names>Marcus J.</given-names></name><xref ref-type="aff" rid="aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Page</surname><given-names>Carly</given-names></name><xref ref-type="aff" rid="aff1">2</xref></contrib><contrib contrib-type="author"><name><surname>Baric</surname><given-names>Ralph S.</given-names></name><xref ref-type="aff" rid="aff1">3</xref></contrib><contrib contrib-type="author"><name><surname>Katze</surname><given-names>Michael G.</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib></contrib-group><aff id="aff1">Department of Microbiology, School of Medicine, University of Washington, Seattle, Washington 98195,<label>1</label> Department of Microbiology and Immunology, University of Maryland, Baltimore, Maryland 21202,<label>2</label> Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599<label>3</label></aff><author-notes><corresp id="cor1"><label>*</label>Corresponding author. Mailing address: Department of Microbiology, School of Medicine, University of Washington, Box 358070, Seattle, WA 98195-8070. Phone: (206) 732-6135. Fax: (206) 543-8297. E-mail: <email>honey@u.washington.edu</email></corresp><fn id="fn3"><label>‡</label><p>G.A.Z. and M.B.F. contributed equally to this work.</p></fn><fn id="fn2"><label>¶</label><p>Present address: Institute for Systems Biology, Seattle, WA.</p></fn></author-notes><pub-date pub-type="ppub"><month>11</month><year>2010</year></pub-date><pub-date pub-type="epub"><day>11</day><month>8</month><year>2010</year></pub-date><volume>84</volume><issue>21</issue><fpage>11297</fpage><lpage>11309</lpage><history><date date-type="received"><day>26</day><month>5</month><year>2010</year></date><date date-type="accepted"><day>5</day><month>8</month><year>2010</year></date></history><permissions><copyright-statement>Copyright © 2010, American Society for Microbiology</copyright-statement><copyright-year>2010</copyright-year></permissions><self-uri xlink:title="pdf" xlink:href="zjv02110011297.pdf"></self-uri><abstract><p>Severe acute respiratory syndrome coronavirus (SARS-CoV) infection can cause the development of severe end-stage lung disease characterized by acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. The mechanisms by which pulmonary lesions and fibrosis are generated during SARS-CoV infection are not known. Using high-throughput mRNA profiling, we examined the transcriptional response of wild-type (WT), type I interferon receptor knockout (IFNAR1<sup>−/−</sup>), and STAT1 knockout (STAT1<sup>−/−</sup>) mice infected with a recombinant mouse-adapted SARS-CoV (rMA15) to better understand the contribution of specific gene expression changes to disease progression. Despite a deletion of the type I interferon receptor, strong expression of interferon-stimulated genes was observed in the lungs of IFNAR1<sup>−/−</sup> mice, contributing to clearance of the virus. In contrast, STAT1<sup>−/−</sup> mice exhibited a defect in the expression of interferon-stimulated genes and were unable to clear the infection, resulting in a lethal outcome. STAT1<sup>−/−</sup> mice exhibited dysregulation of T-cell and macrophage differentiation, leading to a T<sub>H</sub>2-biased immune response and the development of alternatively activated macrophages that mediate a profibrotic environment within the lung. We propose that a combination of impaired viral clearance and T-cell/macrophage dysregulation causes the formation of prefibrotic lesions in the lungs of rMA15-infected STAT1<sup>−/−</sup> mice.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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