Antagonism of dsRNA-Induced Innate Immune Pathways by NS4a and NS4b Accessory Proteins during MERS Coronavirus Infection
Identifieur interne : 000399 ( Pmc/Checkpoint ); précédent : 000398; suivant : 000400Antagonism of dsRNA-Induced Innate Immune Pathways by NS4a and NS4b Accessory Proteins during MERS Coronavirus Infection
Auteurs : Courtney E. Comar [États-Unis] ; Stephen A. Goldstein [États-Unis] ; Yize Li [États-Unis] ; Boyd Yount [États-Unis] ; Ralph S. Baric [États-Unis] ; Susan R. Weiss [États-Unis]Source :
- mBio [ 2150-7511 ] ; 2019.
Abstract
Middle East respiratory syndrome coronavirus (MERS-CoV) is the second novel zoonotic coronavirus to emerge in the 21st century and cause outbreaks of severe respiratory disease. More than 2,200 cases and 800 deaths have been reported to date, yet there are no licensed vaccines or treatments. Coronaviruses encode unique accessory proteins that are not required for replication but most likely play roles in immune antagonism and/or pathogenesis. Our study describes the functions of MERS-CoV accessory proteins NS4a and NS4b during infection of a human airway-derived cell line. Loss of these accessory proteins during MERS-CoV infection leads to host antiviral activation and modestly attenuates replication. In the case of both NS4a and NS4b, we have identified roles during infection not previously described, yet the lack of robust activation suggests much remains to be learned about the interactions between MERS-CoV and the infected host.
Url:
DOI: 10.1128/mBio.00319-19
PubMed: 30914508
PubMed Central: 6437052
Affiliations:
- États-Unis
- Caroline du Nord, Pennsylvanie
- Chapel Hill (Caroline du Nord)
- Université de Caroline du Nord à Chapel Hill
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PMC:6437052Le document en format XML
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Weiss</name><affiliation wicri:level="2"><nlm:aff id="aff1"><addr-line>Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania</wicri:regionArea><placeName><region type="state">Pennsylvanie</region></placeName></affiliation></author></analytic><series><title level="j">mBio</title><idno type="eISSN">2150-7511</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Middle East respiratory syndrome coronavirus (MERS-CoV) is the second novel zoonotic coronavirus to emerge in the 21st century and cause outbreaks of severe respiratory disease. More than 2,200 cases and 800 deaths have been reported to date, yet there are no licensed vaccines or treatments. Coronaviruses encode unique accessory proteins that are not required for replication but most likely play roles in immune antagonism and/or pathogenesis. Our study describes the functions of MERS-CoV accessory proteins NS4a and NS4b during infection of a human airway-derived cell line. Loss of these accessory proteins during MERS-CoV infection leads to host antiviral activation and modestly attenuates replication. In the case of both NS4a and NS4b, we have identified roles during infection not previously described, yet the lack of robust activation suggests much remains to be learned about the interactions between MERS-CoV and the infected host.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Van Boheemen, S" uniqKey="Van Boheemen S">S van Boheemen</name></author><author><name sortKey="De Graaf, M" uniqKey="De Graaf M">M de Graaf</name></author><author><name sortKey="Lauber, C" uniqKey="Lauber C">C Lauber</name></author><author><name sortKey="Bestebroer, Tm" uniqKey="Bestebroer T">TM Bestebroer</name></author><author><name sortKey="Raj, Vs" uniqKey="Raj V">VS Raj</name></author><author><name sortKey="Zaki, Am" uniqKey="Zaki A">AM Zaki</name></author><author><name sortKey="Osterhaus, Adme" uniqKey="Osterhaus A">ADME Osterhaus</name></author><author><name sortKey="Haagmans, Bl" uniqKey="Haagmans B">BL Haagmans</name></author><author><name 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<front><journal-meta><journal-id journal-id-type="nlm-ta">mBio</journal-id><journal-id journal-id-type="iso-abbrev">MBio</journal-id><journal-id journal-id-type="hwp">mbio</journal-id><journal-id journal-id-type="pmc">mbio</journal-id><journal-id journal-id-type="publisher-id">mBio</journal-id><journal-title-group><journal-title>mBio</journal-title></journal-title-group><issn pub-type="epub">2150-7511</issn><publisher><publisher-name>American Society for Microbiology</publisher-name><publisher-loc>1752 N St., N.W., Washington, DC</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">30914508</article-id><article-id pub-id-type="pmc">6437052</article-id><article-id pub-id-type="publisher-id">mBio00319-19</article-id><article-id pub-id-type="doi">10.1128/mBio.00319-19</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="overline"><subject>Host-Microbe Biology</subject></subj-group></article-categories><title-group><article-title>Antagonism of dsRNA-Induced Innate Immune Pathways by NS4a and NS4b Accessory Proteins during MERS Coronavirus Infection</article-title><alt-title alt-title-type="running-head">MERS-CoV NS4a and NS4b Antagonize Innate Immunity</alt-title><alt-title alt-title-type="short-authors">Comar et al.</alt-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Comar</surname><given-names>Courtney E.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Goldstein</surname><given-names>Stephen A.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author" equal-contrib="no"><name><surname>Li</surname><given-names>Yize</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author" equal-contrib="no"><name><surname>Yount</surname><given-names>Boyd</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author" equal-contrib="no"><name><surname>Baric</surname><given-names>Ralph S.</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author" corresp="yes" equal-contrib="no"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-8155-4528</contrib-id><name><surname>Weiss</surname><given-names>Susan R.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><aff id="aff1"><label>a</label><addr-line>Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA</addr-line></aff><aff id="aff2"><label>b</label><addr-line>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA</addr-line></aff><aff id="aff3"><label>c</label><addr-line>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA</addr-line></aff></contrib-group><contrib-group><contrib contrib-type="editor"><name><surname>Palese</surname><given-names>Peter</given-names></name><role>Editor</role><aff>Icahn School of Medicine at Mount Sinai</aff></contrib></contrib-group><contrib-group><contrib contrib-type="reviewer"><name><surname>Perlman</surname><given-names>Stanley</given-names></name><role>Solicited external reviewer</role><aff>University of Iowa</aff></contrib><contrib contrib-type="reviewer"><name><surname>Hogue</surname><given-names>Brenda</given-names></name><role>Solicited external reviewer</role><aff>Arizona State University</aff></contrib></contrib-group><author-notes><corresp id="cor1">Address correspondence to Susan R. Weiss, <email>weisssr@pennmedicine.upenn.edu</email>.</corresp><fn fn-type="equal"><p>C.E.C. and S.A.G. contributed equally to this article.</p></fn></author-notes><pub-date pub-type="epub"><day>26</day><month>3</month><year>2019</year></pub-date><pub-date pub-type="collection"><season>Mar-Apr</season><year>2019</year></pub-date><volume>10</volume><issue>2</issue><elocation-id>e00319-19</elocation-id><history><date date-type="received"><day>4</day><month>2</month><year>2019</year></date><date date-type="accepted"><day>13</day><month>2</month><year>2019</year></date></history><permissions><copyright-statement>Copyright © 2019 Comar et al.</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>Comar et al.</copyright-holder><license license-type="open-access" xlink:href="https://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the <ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by/4.0/">Creative Commons Attribution 4.0 International license</ext-link>.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="mBio.00319-19.pdf"></self-uri><abstract abstract-type="precis"><p>Middle East respiratory syndrome coronavirus (MERS-CoV) is the second novel zoonotic coronavirus to emerge in the 21st century and cause outbreaks of severe respiratory disease. More than 2,200 cases and 800 deaths have been reported to date, yet there are no licensed vaccines or treatments. Coronaviruses encode unique accessory proteins that are not required for replication but most likely play roles in immune antagonism and/or pathogenesis. Our study describes the functions of MERS-CoV accessory proteins NS4a and NS4b during infection of a human airway-derived cell line. Loss of these accessory proteins during MERS-CoV infection leads to host antiviral activation and modestly attenuates replication. In the case of both NS4a and NS4b, we have identified roles during infection not previously described, yet the lack of robust activation suggests much remains to be learned about the interactions between MERS-CoV and the infected host.</p></abstract><abstract><title>ABSTRACT</title><p>Middle East respiratory syndrome coronavirus (MERS-CoV) was first identified in 2012 as a novel etiological agent of severe respiratory disease in humans. As during infection by other viruses, host sensing of viral double-stranded RNA (dsRNA) induces several antiviral pathways. These include interferon (IFN), oligoadenylate synthetase (OAS)-RNase L, and protein kinase R (PKR). Coronaviruses, including MERS-CoV, potently suppress the activation of these pathways, inducing only modest host responses. Our study describes the functions of two accessory proteins unique to MERS-CoV and related viruses, NS4a and NS4b, during infection in human airway epithelium-derived A549 cells. NS4a has been previously characterized as a dsRNA binding protein, while NS4b is a 2′,5′-phosphodiesterase with structural and enzymatic similarity to NS2 encoded by mouse hepatitis virus (MHV). We found that deletion of NS4a results in increased interferon lambda (<italic>IFNL1</italic>) expression, as does mutation of either the catalytic site or nuclear localization sequence of NS4b. All of the mutant viruses we tested exhibited slight decreases in replication. We previously reported that, like MHV NS2, NS4b antagonizes OAS-RNase L, but suppression of IFN is a previously unidentified function for viral phosphodiesterases. Unexpectedly, deletion of NS4a does not result in robust activation of the PKR or OAS-RNase L pathways. Therefore, MERS-CoV likely encodes other proteins that contribute to suppression or evasion of these antiviral innate immune pathways that should be an important focus of future work. This study provides additional insight into the complex interactions between MERS-CoV and the host immune response.</p></abstract><kwd-group><title>KEYWORDS</title><kwd>MERS-CoV</kwd><kwd>coronavirus</kwd><kwd>interferon antagonist</kwd><kwd>viral accessory proteins</kwd></kwd-group><funding-group><award-group id="award1"><funding-source><institution-wrap><institution>HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)</institution><institution-id>https://doi.org/10.13039/100000060</institution-id></institution-wrap></funding-source><award-id>R01 AI140442</award-id><principal-award-recipient><name><surname>Weiss</surname><given-names>Susan R.</given-names></name></principal-award-recipient><principal-award-recipient><name><surname>Li</surname><given-names>Yize</given-names></name></principal-award-recipient><principal-award-recipient><name><surname>Goldstein</surname><given-names>Stephen A.</given-names></name></principal-award-recipient><principal-award-recipient><name><surname>Comar</surname><given-names>Courtney</given-names></name></principal-award-recipient></award-group><award-group id="award2"><funding-source><institution-wrap><institution>HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)</institution><institution-id>https://doi.org/10.13039/100000060</institution-id></institution-wrap></funding-source><award-id>R21 AI114920</award-id><principal-award-recipient><name><surname>Weiss</surname><given-names>Susan R.</given-names></name></principal-award-recipient><principal-award-recipient><name><surname>Li</surname><given-names>Yize</given-names></name></principal-award-recipient><principal-award-recipient><name><surname>Goldstein</surname><given-names>Stephen A.</given-names></name></principal-award-recipient><principal-award-recipient><name><surname>Comar</surname><given-names>Courtney</given-names></name></principal-award-recipient></award-group><award-group id="award3"><funding-source><institution-wrap><institution>HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)</institution><institution-id>https://doi.org/10.13039/100000060</institution-id></institution-wrap></funding-source><award-id>F31 AI126673</award-id><principal-award-recipient><name><surname>Goldstein</surname><given-names>Stephen A.</given-names></name></principal-award-recipient></award-group><award-group id="award4"><funding-source><institution-wrap><institution>HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)</institution><institution-id>https://doi.org/10.13039/100000060</institution-id></institution-wrap></funding-source><award-id>R01 AI110700</award-id><principal-award-recipient><name><surname>Baric</surname><given-names>Ralph S.</given-names></name></principal-award-recipient><principal-award-recipient><name><surname>Yount</surname><given-names>Boyd</given-names></name></principal-award-recipient></award-group><award-group id="award5"><funding-source><institution-wrap><institution>HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)</institution><institution-id>https://doi.org/10.13039/100000060</institution-id></institution-wrap></funding-source><award-id>U19 AI109761</award-id><principal-award-recipient><name><surname>Baric</surname><given-names>Ralph S.</given-names></name></principal-award-recipient><principal-award-recipient><name><surname>Yount</surname><given-names>Boyd</given-names></name></principal-award-recipient></award-group></funding-group><counts><fig-count count="9"></fig-count><table-count count="0"></table-count><equation-count count="0"></equation-count><ref-count count="47"></ref-count><page-count count="16"></page-count><word-count count="9752"></word-count></counts><custom-meta-group><custom-meta><meta-name>cover-date</meta-name><meta-value>March/April 2019</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc><affiliations><list><country><li>États-Unis</li></country><region><li>Caroline du Nord</li><li>Pennsylvanie</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="Pennsylvanie"><name sortKey="Comar, Courtney E" sort="Comar, Courtney E" uniqKey="Comar C" first="Courtney E." last="Comar">Courtney E. Comar</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="Goldstein, Stephen A" sort="Goldstein, Stephen A" uniqKey="Goldstein S" first="Stephen A." last="Goldstein">Stephen A. Goldstein</name><name sortKey="Li, Yize" sort="Li, Yize" uniqKey="Li Y" first="Yize" last="Li">Yize Li</name><name sortKey="Weiss, Susan R" sort="Weiss, Susan R" uniqKey="Weiss S" first="Susan R." last="Weiss">Susan R. Weiss</name><name sortKey="Yount, Boyd" sort="Yount, Boyd" uniqKey="Yount B" first="Boyd" last="Yount">Boyd Yount</name><name sortKey="Yount, Boyd" sort="Yount, Boyd" uniqKey="Yount B" first="Boyd" last="Yount">Boyd Yount</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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