MyD88 Is Required for Protection from Lethal Infection with a Mouse-Adapted SARS-CoV
Identifieur interne : 000E02 ( Pmc/Checkpoint ); précédent : 000E01; suivant : 000E03MyD88 Is Required for Protection from Lethal Infection with a Mouse-Adapted SARS-CoV
Auteurs : Timothy Sheahan [États-Unis] ; Thomas E. Morrison [États-Unis] ; William Funkhouser [États-Unis] ; Satoshi Uematsu [Japon] ; Shizou Akira [Japon] ; Ralph S. Baric [États-Unis] ; Mark T. Heise [États-Unis]Source :
- PLoS Pathogens [ 1553-7366 ] ; 2008.
Abstract
A novel human coronavirus, SARS-CoV, emerged suddenly in 2003, causing approximately 8000 human cases and more than 700 deaths worldwide. Since most animal models fail to faithfully recapitulate the clinical course of SARS-CoV in humans, the virus and host factors that mediate disease pathogenesis remain unclear. Recently, our laboratory and others developed a recombinant mouse-adapted SARS-CoV (rMA15) that was lethal in BALB/c mice. In contrast, intranasal infection of young 10-week-old C57BL/6 mice with rMA15 results in a nonlethal infection characterized by high titer replication within the lungs, lung inflammation, destruction of lung tissue, and loss of body weight, thus providing a useful model to identify host mediators of protection. Here, we report that mice deficient in MyD88 (MyD88−/−), an adapter protein that mediates Toll-like receptor (TLR), IL-1R, and IL-18R signaling, are far more susceptible to rMA15 infection. The genetic absence of MyD88 resulted in enhanced pulmonary pathology and greater than 90% mortality by day 6 post-infection. MyD88−/− mice had significantly higher viral loads in lung tissue throughout the course of infection. Despite increased viral loads, the expression of multiple proinflammatory cytokines and chemokines within lung tissue and recruitment of inflammatory monocytes/macrophages to the lung was severely impaired in MyD88−/− mice compared to wild-type mice. Furthermore, mice deficient in chemokine receptors that contribute to monocyte recruitment to the lung were more susceptible to rMA15-induced disease and exhibited severe lung pathology similar to that seen in MyD88−/−mice. These data suggest that MyD88-mediated innate immune signaling and inflammatory cell recruitment to the lung are required for protection from lethal rMA15 infection.
Url:
DOI: 10.1371/journal.ppat.1000240
PubMed: 19079579
PubMed Central: 2587915
Affiliations:
- Japon, États-Unis
- Caroline du Nord
- Chapel Hill (Caroline du Nord)
- Université de Caroline du Nord à Chapel Hill
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PMC:2587915Le document en format XML
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<front><div type="abstract" xml:lang="en"><p>A novel human coronavirus, SARS-CoV, emerged suddenly in 2003, causing approximately 8000 human cases and more than 700 deaths worldwide. Since most animal models fail to faithfully recapitulate the clinical course of SARS-CoV in humans, the virus and host factors that mediate disease pathogenesis remain unclear. Recently, our laboratory and others developed a recombinant mouse-adapted SARS-CoV (rMA15) that was lethal in BALB/c mice. In contrast, intranasal infection of young 10-week-old C57BL/6 mice with rMA15 results in a nonlethal infection characterized by high titer replication within the lungs, lung inflammation, destruction of lung tissue, and loss of body weight, thus providing a useful model to identify host mediators of protection. Here, we report that mice deficient in MyD88 (MyD88<sup>−/−</sup>
), an adapter protein that mediates Toll-like receptor (TLR), IL-1R, and IL-18R signaling, are far more susceptible to rMA15 infection. The genetic absence of MyD88 resulted in enhanced pulmonary pathology and greater than 90% mortality by day 6 post-infection. MyD88<sup>−/−</sup>
mice had significantly higher viral loads in lung tissue throughout the course of infection. Despite increased viral loads, the expression of multiple proinflammatory cytokines and chemokines within lung tissue and recruitment of inflammatory monocytes/macrophages to the lung was severely impaired in MyD88<sup>−/−</sup>
mice compared to wild-type mice. Furthermore, mice deficient in chemokine receptors that contribute to monocyte recruitment to the lung were more susceptible to rMA15-induced disease and exhibited severe lung pathology similar to that seen in MyD88<sup>−/−</sup>
mice. These data suggest that MyD88-mediated innate immune signaling and inflammatory cell recruitment to the lung are required for protection from lethal rMA15 infection.</p>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Pathog</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS Pathog</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">plospath</journal-id>
<journal-title-group><journal-title>PLoS Pathogens</journal-title>
</journal-title-group>
<issn pub-type="ppub">1553-7366</issn>
<issn pub-type="epub">1553-7374</issn>
<publisher><publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">19079579</article-id>
<article-id pub-id-type="pmc">2587915</article-id>
<article-id pub-id-type="publisher-id">08-PLPA-RA-0634R2</article-id>
<article-id pub-id-type="doi">10.1371/journal.ppat.1000240</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
<subj-group subj-group-type="Discipline"><subject>Immunology/Cellular Microbiology and Pathogenesis</subject>
<subject>Immunology/Genetics of the Immune System</subject>
<subject>Immunology/Immune Response</subject>
<subject>Immunology/Innate Immunity</subject>
<subject>Virology/Animal Models of Infection</subject>
<subject>Virology/Effects of Virus Infection on Host Gene Expression</subject>
<subject>Virology/Emerging Viral Diseases</subject>
<subject>Virology/Mechanisms of Resistance and Susceptibility, including Host Genetics</subject>
</subj-group>
</article-categories>
<title-group><article-title>MyD88 Is Required for Protection from Lethal Infection with a Mouse-Adapted SARS-CoV</article-title>
<alt-title alt-title-type="running-head">MyD88 Protects from Lethal Infection with SARS-CoV</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Sheahan</surname>
<given-names>Timothy</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes"><name><surname>Morrison</surname>
<given-names>Thomas E.</given-names>
</name>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
<xref ref-type="aff" rid="aff4"><sup>4</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Funkhouser</surname>
<given-names>William</given-names>
</name>
<xref ref-type="aff" rid="aff5"><sup>5</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Uematsu</surname>
<given-names>Satoshi</given-names>
</name>
<xref ref-type="aff" rid="aff6"><sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Akira</surname>
<given-names>Shizou</given-names>
</name>
<xref ref-type="aff" rid="aff6"><sup>6</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Baric</surname>
<given-names>Ralph S.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff2"><sup>2</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>*</sup>
</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Heise</surname>
<given-names>Mark T.</given-names>
</name>
<xref ref-type="aff" rid="aff1"><sup>1</sup>
</xref>
<xref ref-type="aff" rid="aff3"><sup>3</sup>
</xref>
<xref ref-type="aff" rid="aff4"><sup>4</sup>
</xref>
<xref ref-type="corresp" rid="cor1"><sup>*</sup>
</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>1</label>
<addr-line>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line>
</aff>
<aff id="aff2"><label>2</label>
<addr-line>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line>
</aff>
<aff id="aff3"><label>3</label>
<addr-line>Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line>
</aff>
<aff id="aff4"><label>4</label>
<addr-line>Carolina Vaccine Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America</addr-line>
</aff>
<aff id="aff5"><label>5</label>
<addr-line>Department of Pathology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America</addr-line>
</aff>
<aff id="aff6"><label>6</label>
<addr-line>WPI Immunology Frontier Research Center, Laboratory of Host Defense, Osaka University, Suita, Osaka, Japan</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Subbarao</surname>
<given-names>Kanta</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1">National Institutes of Health, United States of America</aff>
<author-notes><corresp id="cor1">* E-mail: <email>rbaric@email.unc.edu</email>
(RSB); <email>heisem@med.unc.edu</email>
(MTH)</corresp>
<fn fn-type="con"><p>Conceived and designed the experiments: TS TEM RSB MTH. Performed the experiments: TS TEM. Analyzed the data: TS TEM WF. Contributed reagents/materials/analysis tools: SU SA. Wrote the paper: TS TEM WF RSB MTH.</p>
</fn>
</author-notes>
<pub-date pub-type="collection"><month>12</month>
<year>2008</year>
</pub-date>
<pub-date pub-type="epub"><day>12</day>
<month>12</month>
<year>2008</year>
</pub-date>
<volume>4</volume>
<issue>12</issue>
<elocation-id>e1000240</elocation-id>
<history><date date-type="received"><day>19</day>
<month>6</month>
<year>2008</year>
</date>
<date date-type="accepted"><day>13</day>
<month>11</month>
<year>2008</year>
</date>
</history>
<permissions><copyright-statement>Sheahan et al.</copyright-statement>
<copyright-year>2008</copyright-year>
<license 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 properly credited.</license-p>
</license>
</permissions>
<abstract><p>A novel human coronavirus, SARS-CoV, emerged suddenly in 2003, causing approximately 8000 human cases and more than 700 deaths worldwide. Since most animal models fail to faithfully recapitulate the clinical course of SARS-CoV in humans, the virus and host factors that mediate disease pathogenesis remain unclear. Recently, our laboratory and others developed a recombinant mouse-adapted SARS-CoV (rMA15) that was lethal in BALB/c mice. In contrast, intranasal infection of young 10-week-old C57BL/6 mice with rMA15 results in a nonlethal infection characterized by high titer replication within the lungs, lung inflammation, destruction of lung tissue, and loss of body weight, thus providing a useful model to identify host mediators of protection. Here, we report that mice deficient in MyD88 (MyD88<sup>−/−</sup>
), an adapter protein that mediates Toll-like receptor (TLR), IL-1R, and IL-18R signaling, are far more susceptible to rMA15 infection. The genetic absence of MyD88 resulted in enhanced pulmonary pathology and greater than 90% mortality by day 6 post-infection. MyD88<sup>−/−</sup>
mice had significantly higher viral loads in lung tissue throughout the course of infection. Despite increased viral loads, the expression of multiple proinflammatory cytokines and chemokines within lung tissue and recruitment of inflammatory monocytes/macrophages to the lung was severely impaired in MyD88<sup>−/−</sup>
mice compared to wild-type mice. Furthermore, mice deficient in chemokine receptors that contribute to monocyte recruitment to the lung were more susceptible to rMA15-induced disease and exhibited severe lung pathology similar to that seen in MyD88<sup>−/−</sup>
mice. These data suggest that MyD88-mediated innate immune signaling and inflammatory cell recruitment to the lung are required for protection from lethal rMA15 infection.</p>
</abstract>
<abstract abstract-type="summary"><title>Author Summary</title>
<p>In 2002, a new human coronavirus (CoV), termed SARS-CoV, emerged in southern China from coronaviruses circulating within live animals sold for food. Due to the ease and speed of human global travel, this new respiratory virus rapidly spread worldwide, illustrating the need to better understand how these viruses cause disease and how the immune system responds to infection. SARS-CoV infection of the human lower respiratory tract caused an atypical pneumonia characterized by viral replication in lung tissue and lung inflammation visible by chest X-ray. To identify how the immune system responds to and provides protection from SARS-CoV infection, we have developed a mouse model that mimics many aspects of SARS-CoV disease in humans. Utilizing this mouse model, we discovered that a host gene, termed MyD88, is required to control SARS-CoV replication and spread in lung tissue and for protection from death. In addition, MyD88-dependent functions were required for early immune and inflammatory responses in the lung following SARS-CoV infection, and the absence of these early responses correlated with severe SARS-CoV-induced disease and death. Our studies identify host immune responses that provide protection from SARS-CoV infection and provide valuable insight toward the development of successful antiviral therapies.</p>
</abstract>
<counts><page-count count="12"></page-count>
</counts>
</article-meta>
</front>
</pmc>
<affiliations><list><country><li>Japon</li>
<li>États-Unis</li>
</country>
<region><li>Caroline du Nord</li>
</region>
<settlement><li>Chapel Hill (Caroline du Nord)</li>
</settlement>
<orgName><li>Université de Caroline du Nord à Chapel Hill</li>
</orgName>
</list>
<tree><country name="États-Unis"><region name="Caroline du Nord"><name sortKey="Sheahan, Timothy" sort="Sheahan, Timothy" uniqKey="Sheahan T" first="Timothy" last="Sheahan">Timothy Sheahan</name>
</region>
<name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name>
<name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S." last="Baric">Ralph S. Baric</name>
<name sortKey="Funkhouser, William" sort="Funkhouser, William" uniqKey="Funkhouser W" first="William" last="Funkhouser">William Funkhouser</name>
<name sortKey="Heise, Mark T" sort="Heise, Mark T" uniqKey="Heise M" first="Mark T." last="Heise">Mark T. Heise</name>
<name sortKey="Heise, Mark T" sort="Heise, Mark T" uniqKey="Heise M" first="Mark T." last="Heise">Mark T. Heise</name>
<name sortKey="Heise, Mark T" sort="Heise, Mark T" uniqKey="Heise M" first="Mark T." last="Heise">Mark T. Heise</name>
<name sortKey="Morrison, Thomas E" sort="Morrison, Thomas E" uniqKey="Morrison T" first="Thomas E." last="Morrison">Thomas E. Morrison</name>
<name sortKey="Morrison, Thomas E" sort="Morrison, Thomas E" uniqKey="Morrison T" first="Thomas E." last="Morrison">Thomas E. Morrison</name>
<name sortKey="Sheahan, Timothy" sort="Sheahan, Timothy" uniqKey="Sheahan T" first="Timothy" last="Sheahan">Timothy Sheahan</name>
</country>
<country name="Japon"><noRegion><name sortKey="Uematsu, Satoshi" sort="Uematsu, Satoshi" uniqKey="Uematsu S" first="Satoshi" last="Uematsu">Satoshi Uematsu</name>
</noRegion>
<name sortKey="Akira, Shizou" sort="Akira, Shizou" uniqKey="Akira S" first="Shizou" last="Akira">Shizou Akira</name>
</country>
</tree>
</affiliations>
</record>
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