Middle East Respiratory Syndrome Coronavirus Nonstructural Protein 16 Is Necessary for Interferon Resistance and Viral Pathogenesis
Identifieur interne : 001638 ( Pmc/Curation ); précédent : 001637; suivant : 001639Middle East Respiratory Syndrome Coronavirus Nonstructural Protein 16 Is Necessary for Interferon Resistance and Viral Pathogenesis
Auteurs : Vineet D. Menachery [États-Unis] ; Lisa E. Gralinski [États-Unis] ; Hugh D. Mitchell [États-Unis] ; Kenneth H. Dinnon [États-Unis] ; Sarah R. Leist [États-Unis] ; Boyd L. Yount [États-Unis] ; Rachel L. Graham [États-Unis] ; Eileen T. Mcanarney [États-Unis] ; Kelly G. Stratton [États-Unis] ; Adam S. Cockrell [États-Unis] ; Kari Debbink [États-Unis] ; Amy C. Sims [États-Unis] ; Katrina M. Waters [États-Unis] ; Ralph S. Baric [États-Unis]Source :
- mSphere [ 2379-5042 ] ; 2017.
Abstract
Coronavirus (CoV) emergence in both humans and livestock represents a significant threat to global public health, as evidenced by the sudden emergence of severe acute respiratory syndrome CoV (SARS-CoV), MERS-CoV, porcine epidemic diarrhea virus, and swine delta CoV in the 21st century. These studies describe an approach that effectively targets the highly conserved 2′
Url:
DOI: 10.1128/mSphere.00346-17
PubMed: 29152578
PubMed Central: 5687918
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Mcanarney</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea></affiliation></author><author><name sortKey="Stratton, Kelly G" sort="Stratton, Kelly G" uniqKey="Stratton K" first="Kelly G." last="Stratton">Kelly G. Stratton</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Pacific Northwest National Laboratory, Richland, Washington, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Pacific Northwest National Laboratory, Richland, Washington</wicri:regionArea></affiliation></author><author><name sortKey="Cockrell, Adam S" sort="Cockrell, Adam S" uniqKey="Cockrell A" first="Adam S." last="Cockrell">Adam S. Cockrell</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea></affiliation></author><author><name sortKey="Debbink, Kari" sort="Debbink, Kari" uniqKey="Debbink K" first="Kari" last="Debbink">Kari Debbink</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>Department of Natural Sciences, Bowie State University, Bowie, Maryland, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Natural Sciences, Bowie State University, Bowie, Maryland</wicri:regionArea></affiliation></author><author><name sortKey="Sims, Amy C" sort="Sims, Amy C" uniqKey="Sims A" first="Amy C." last="Sims">Amy C. Sims</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea></affiliation></author><author><name sortKey="Waters, Katrina M" sort="Waters, Katrina M" uniqKey="Waters K" first="Katrina M." last="Waters">Katrina M. Waters</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Pacific Northwest National Laboratory, Richland, Washington, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Pacific Northwest National Laboratory, Richland, Washington</wicri:regionArea></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 wicri:level="1"><nlm:aff id="aff2"><addr-line>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina</wicri:regionArea></affiliation></author></analytic><series><title level="j">mSphere</title><idno type="eISSN">2379-5042</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Coronavirus (CoV) emergence in both humans and livestock represents a significant threat to global public health, as evidenced by the sudden emergence of severe acute respiratory syndrome CoV (SARS-CoV), MERS-CoV, porcine epidemic diarrhea virus, and swine delta CoV in the 21st century. These studies describe an approach that effectively targets the highly conserved 2′<italic>O</italic>-MTase activity of CoVs for attenuation. With clear understanding of the IFN/IFIT (IFN-induced proteins with tetratricopeptide repeats)-based mechanism, NSP16 mutants provide a suitable target for a live attenuated vaccine platform, as well as therapeutic development for both current and future emergent CoV strains. Importantly, other approaches targeting other conserved pan-CoV functions have not yet proven effective against MERS-CoV, illustrating the broad applicability of targeting viral 2′<italic>O</italic>-MTase function across CoVs.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Vijay, R" uniqKey="Vijay R">R Vijay</name></author><author><name sortKey="Perlman, S" uniqKey="Perlman S">S Perlman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zumla, A" uniqKey="Zumla A">A Zumla</name></author><author><name sortKey="Hui, Ds" uniqKey="Hui D">DS Hui</name></author><author><name sortKey="Perlman, S" uniqKey="Perlman S">S Perlman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Okba, Nm" uniqKey="Okba N">NM Okba</name></author><author><name sortKey="Raj, Vs" uniqKey="Raj V">VS Raj</name></author><author><name sortKey="Haagmans, Bl" uniqKey="Haagmans B">BL 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Metz</name></author><author><name sortKey="Pickles, R" uniqKey="Pickles R">R Pickles</name></author><author><name sortKey="Mcweeney, S" uniqKey="Mcweeney S">S McWeeney</name></author><author><name sortKey="Smith, Rd" uniqKey="Smith R">RD Smith</name></author><author><name sortKey="Katze, Mg" uniqKey="Katze M">MG Katze</name></author><author><name sortKey="Waters, Km" uniqKey="Waters K">KM Waters</name></author><author><name sortKey="Baric, Rs" uniqKey="Baric R">RS Baric</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, Y" uniqKey="Chen Y">Y Chen</name></author><author><name sortKey="Su, C" uniqKey="Su C">C Su</name></author><author><name sortKey="Ke, M" uniqKey="Ke M">M Ke</name></author><author><name sortKey="Jin, X" uniqKey="Jin X">X Jin</name></author><author><name sortKey="Xu, L" uniqKey="Xu L">L Xu</name></author><author><name sortKey="Zhang, Z" uniqKey="Zhang Z">Z Zhang</name></author><author><name sortKey="Wu, A" uniqKey="Wu A">A 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<front><journal-meta><journal-id journal-id-type="nlm-ta">mSphere</journal-id><journal-id journal-id-type="iso-abbrev">mSphere</journal-id><journal-id journal-id-type="hwp">msph</journal-id><journal-id journal-id-type="pmc">msph</journal-id><journal-id journal-id-type="publisher-id">mSphere</journal-id><journal-title-group><journal-title>mSphere</journal-title></journal-title-group><issn pub-type="epub">2379-5042</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">29152578</article-id><article-id pub-id-type="pmc">5687918</article-id><article-id pub-id-type="publisher-id">mSphere00346-17</article-id><article-id pub-id-type="doi">10.1128/mSphere.00346-17</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject><subj-group><subject>Host-Microbe Biology</subject></subj-group></subj-group></article-categories><title-group><article-title>Middle East Respiratory Syndrome Coronavirus Nonstructural Protein 16 Is Necessary for Interferon Resistance and Viral Pathogenesis</article-title><alt-title alt-title-type="running-head">MERS-CoV NSP16 Is Necessary for Pathogenesis</alt-title><alt-title alt-title-type="short-authors">Menachery et al.</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Menachery</surname><given-names>Vineet D.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gralinski</surname><given-names>Lisa E.</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mitchell</surname><given-names>Hugh D.</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dinnon</surname><given-names>Kenneth H.</given-names><suffix>III</suffix></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Leist</surname><given-names>Sarah R.</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Yount</surname><given-names>Boyd L.</given-names><suffix>Jr.</suffix></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Graham</surname><given-names>Rachel L.</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>McAnarney</surname><given-names>Eileen T.</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Stratton</surname><given-names>Kelly G.</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cockrell</surname><given-names>Adam S.</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Debbink</surname><given-names>Kari</given-names></name><xref ref-type="aff" rid="aff5"><sup>e</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sims</surname><given-names>Amy C.</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Waters</surname><given-names>Katrina M.</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref></contrib><contrib contrib-type="author" corresp="yes"><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><aff id="aff1"><label>a</label><addr-line>Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, 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><aff id="aff4"><label>d</label><addr-line>Pacific Northwest National Laboratory, Richland, Washington, USA</addr-line></aff><aff id="aff5"><label>e</label><addr-line>Department of Natural Sciences, Bowie State University, Bowie, Maryland, USA</addr-line></aff></contrib-group><contrib-group><contrib contrib-type="editor"><name><surname>Fernandez-Sesma</surname><given-names>Ana</given-names></name><role>Editor</role><aff>Icahn School of Medicine at Mount Sinai</aff></contrib></contrib-group><author-notes><corresp id="cor1">Address correspondence to Ralph S. Baric, <email>Rbaric@email.unc.edu</email>.</corresp><fn fn-type="other"><p><bold>Citation</bold> Menachery VD, Gralinski LE, Mitchell HD, Dinnon KH, III, Leist SR, Yount BL, Jr, Graham RL, McAnarney ET, Stratton KG, Cockrell AS, Debbink K, Sims AC, Waters KM, Baric RS. 2017. Middle East respiratory syndrome coronavirus nonstructural protein 16 is necessary for interferon resistance and viral pathogenesis. mSphere 2:e00346-17. <ext-link ext-link-type="uri" xlink:href="https://doi.org/10.1128/mSphere.00346-17">https://doi.org/10.1128/mSphere.00346-17</ext-link>.</p></fn></author-notes><pub-date pub-type="epub"><day>15</day><month>11</month><year>2017</year></pub-date><pub-date pub-type="collection"><season>Nov-Dec</season><year>2017</year></pub-date><volume>2</volume><issue>6</issue><elocation-id>e00346-17</elocation-id><history><date date-type="received"><day>8</day><month>8</month><year>2017</year></date><date date-type="accepted"><day>26</day><month>10</month><year>2017</year></date></history><permissions><copyright-statement>Copyright © 2017 Menachery et al.</copyright-statement><copyright-year>2017</copyright-year><copyright-holder>Menachery 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="sph006172404001.pdf"></self-uri><abstract abstract-type="precis"><p>Coronavirus (CoV) emergence in both humans and livestock represents a significant threat to global public health, as evidenced by the sudden emergence of severe acute respiratory syndrome CoV (SARS-CoV), MERS-CoV, porcine epidemic diarrhea virus, and swine delta CoV in the 21st century. These studies describe an approach that effectively targets the highly conserved 2′<italic>O</italic>-MTase activity of CoVs for attenuation. With clear understanding of the IFN/IFIT (IFN-induced proteins with tetratricopeptide repeats)-based mechanism, NSP16 mutants provide a suitable target for a live attenuated vaccine platform, as well as therapeutic development for both current and future emergent CoV strains. Importantly, other approaches targeting other conserved pan-CoV functions have not yet proven effective against MERS-CoV, illustrating the broad applicability of targeting viral 2′<italic>O</italic>-MTase function across CoVs.</p></abstract><abstract><title>ABSTRACT</title><p>Coronaviruses (CoVs) encode a mixture of highly conserved and novel genes, as well as genetic elements necessary for infection and pathogenesis, raising the possibility of common targets for attenuation and therapeutic design. In this study, we focused on highly conserved nonstructural protein 16 (NSP16), a viral 2′<italic>O</italic>-methyltransferase (2′<italic>O</italic>-MTase) that encodes critical functions in immune modulation and infection. Using reverse genetics, we disrupted a key motif in the conserved KDKE motif of Middle East respiratory syndrome CoV (MERS-CoV) NSP16 (D130A) and evaluated the effect on viral infection and pathogenesis. While the absence of 2′<italic>O</italic>-MTase activity had only a marginal impact on propagation and replication in Vero cells, dNSP16 mutant MERS-CoV demonstrated significant attenuation relative to the control both in primary human airway cell cultures and <italic>in vivo</italic>. Further examination indicated that dNSP16 mutant MERS-CoV had a type I interferon (IFN)-based attenuation and was partially restored in the absence of molecules of IFN-induced proteins with tetratricopeptide repeats. Importantly, the robust attenuation permitted the use of dNSP16 mutant MERS-CoV as a live attenuated vaccine platform protecting from a challenge with a mouse-adapted MERS-CoV strain. These studies demonstrate the importance of the conserved 2′<italic>O</italic>-MTase activity for CoV pathogenesis and highlight NSP16 as a conserved universal target for rapid live attenuated vaccine design in an expanding CoV outbreak setting.</p><p><bold>IMPORTANCE</bold> Coronavirus (CoV) emergence in both humans and livestock represents a significant threat to global public health, as evidenced by the sudden emergence of severe acute respiratory syndrome CoV (SARS-CoV), MERS-CoV, porcine epidemic diarrhea virus, and swine delta CoV in the 21st century. These studies describe an approach that effectively targets the highly conserved 2′<italic>O</italic>-MTase activity of CoVs for attenuation. With clear understanding of the IFN/IFIT (IFN-induced proteins with tetratricopeptide repeats)-based mechanism, NSP16 mutants provide a suitable target for a live attenuated vaccine platform, as well as therapeutic development for both current and future emergent CoV strains. Importantly, other approaches targeting other conserved pan-CoV functions have not yet proven effective against MERS-CoV, illustrating the broad applicability of targeting viral 2′<italic>O</italic>-MTase function across CoVs.</p></abstract><kwd-group><title>KEYWORDS</title><kwd>IFIT</kwd><kwd>MERS-CoV</kwd><kwd>SARS-CoV</kwd><kwd>coronavirus</kwd><kwd>emerging virus</kwd><kwd>live attenuated</kwd><kwd>methyltransferase</kwd><kwd>vaccine</kwd></kwd-group><funding-group><award-group id="award1"><funding-source>HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
<named-content content-type="funder-id">https://doi.org/10.13039/100000060</named-content></funding-source><award-id>U19AI100625</award-id><award-id>U19AI106772</award-id><award-id>HHSN272201000019I-HHSN27200003</award-id><principal-award-recipient>Ralph S. Baric</principal-award-recipient></award-group><award-group id="award2"><funding-source>HHS | NIH | National Institute on Aging (NIA)
<named-content content-type="funder-id">https://doi.org/10.13039/100000049</named-content></funding-source><award-id>K99AG049092</award-id><principal-award-recipient>Vineet D. Menachery</principal-award-recipient></award-group></funding-group><counts><fig-count count="6"></fig-count><table-count count="0"></table-count><equation-count count="0"></equation-count><ref-count count="38"></ref-count><page-count count="12"></page-count><word-count count="6817"></word-count></counts><custom-meta-group><custom-meta><meta-name>cover-date</meta-name><meta-value>November/December 2017</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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