Pandemic Influenza A Viruses Escape from Restriction by Human MxA through Adaptive Mutations in the Nucleoprotein
Identifieur interne : 000590 ( Pmc/Checkpoint ); précédent : 000589; suivant : 000591Pandemic Influenza A Viruses Escape from Restriction by Human MxA through Adaptive Mutations in the Nucleoprotein
Auteurs : Benjamin M Nz [Allemagne] ; Dominik Dornfeld [Allemagne] ; Veronika Götz [Allemagne] ; Roland Zell [Allemagne] ; Petra Zimmermann [Allemagne] ; Otto Haller [Allemagne] ; Georg Kochs [Allemagne] ; Martin Schwemmle [Allemagne]Source :
- PLoS Pathogens [ 1553-7366 ] ; 2013.
Abstract
The interferon-induced dynamin-like MxA GTPase restricts the replication of influenza A viruses. We identified adaptive mutations in the nucleoprotein (NP) of pandemic strains A/Brevig Mission/1/1918 (1918) and A/Hamburg/4/2009 (pH1N1) that confer MxA resistance. These resistance-associated amino acids in NP differ between the two strains but form a similar discrete surface-exposed cluster in the body domain of NP, indicating that MxA resistance evolved independently. The 1918 cluster was conserved in all descendent strains of seasonal influenza viruses. Introduction of this cluster into the NP of the MxA-sensitive influenza virus A/Thailand/1(KAN-1)/04 (H5N1) resulted in a gain of MxA resistance coupled with a decrease in viral replication fitness. Conversely, introduction of MxA-sensitive amino acids into pH1N1 NP enhanced viral growth in Mx-negative cells. We conclude that human MxA represents a barrier against zoonotic introduction of avian influenza viruses and that adaptive mutations in the viral NP should be carefully monitored.
Url:
DOI: 10.1371/journal.ppat.1003279
PubMed: 23555271
PubMed Central: 3610643
Affiliations:
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Influenza A Viruses Escape from Restriction by Human MxA through Adaptive Mutations in the Nucleoprotein</title><author><name sortKey="M Nz, Benjamin" sort="M Nz, Benjamin" uniqKey="M Nz B" first="Benjamin" last="M Nz">Benjamin M Nz</name><affiliation wicri:level="3"><nlm:aff id="aff1"><addr-line>Department of Virology, Institute for Medical Microbiology and Hygiene, University of Freiburg, Freiburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Virology, Institute for Medical Microbiology and Hygiene, University of Freiburg, Freiburg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Fribourg-en-Brisgau</region><settlement type="city">Fribourg-en-Brisgau</settlement></placeName></affiliation></author><author><name sortKey="Dornfeld, Dominik" sort="Dornfeld, Dominik" uniqKey="Dornfeld D" first="Dominik" last="Dornfeld">Dominik Dornfeld</name><affiliation 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Institute for Medical Microbiology and Hygiene, University of Freiburg, Freiburg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Fribourg-en-Brisgau</region><settlement type="city">Fribourg-en-Brisgau</settlement></placeName></affiliation></author><author><name sortKey="Zell, Roland" sort="Zell, Roland" uniqKey="Zell R" first="Roland" last="Zell">Roland Zell</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Virology und Antiviral Therapy, Universitätsklinikum Jena, Friedrich Schiller University Jena, Jena, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology und Antiviral Therapy, Universitätsklinikum Jena, Friedrich Schiller University Jena, Jena</wicri:regionArea><wicri:noRegion>Jena</wicri:noRegion><wicri:noRegion>Jena</wicri:noRegion><wicri:noRegion>Jena</wicri:noRegion></affiliation></author><author><name sortKey="Zimmermann, Petra" sort="Zimmermann, Petra" uniqKey="Zimmermann P" first="Petra" last="Zimmermann">Petra Zimmermann</name><affiliation wicri:level="3"><nlm:aff id="aff1"><addr-line>Department of Virology, Institute for Medical Microbiology and Hygiene, University of Freiburg, Freiburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Virology, Institute for Medical Microbiology and Hygiene, University of Freiburg, Freiburg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Fribourg-en-Brisgau</region><settlement type="city">Fribourg-en-Brisgau</settlement></placeName></affiliation></author><author><name sortKey="Haller, Otto" sort="Haller, Otto" uniqKey="Haller O" first="Otto" last="Haller">Otto Haller</name><affiliation wicri:level="3"><nlm:aff id="aff1"><addr-line>Department of Virology, Institute for Medical Microbiology and Hygiene, University of Freiburg, Freiburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Virology, Institute for Medical Microbiology and Hygiene, University of Freiburg, Freiburg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Fribourg-en-Brisgau</region><settlement type="city">Fribourg-en-Brisgau</settlement></placeName></affiliation></author><author><name sortKey="Kochs, Georg" sort="Kochs, Georg" uniqKey="Kochs G" first="Georg" last="Kochs">Georg Kochs</name><affiliation wicri:level="3"><nlm:aff id="aff1"><addr-line>Department of Virology, Institute for Medical Microbiology and Hygiene, University of Freiburg, Freiburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Virology, Institute for Medical Microbiology and Hygiene, University of Freiburg, Freiburg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Fribourg-en-Brisgau</region><settlement type="city">Fribourg-en-Brisgau</settlement></placeName></affiliation></author><author><name sortKey="Schwemmle, Martin" sort="Schwemmle, Martin" uniqKey="Schwemmle M" first="Martin" last="Schwemmle">Martin Schwemmle</name><affiliation wicri:level="3"><nlm:aff id="aff1"><addr-line>Department of Virology, Institute for Medical Microbiology and Hygiene, University of Freiburg, Freiburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Virology, Institute for Medical Microbiology and Hygiene, University of Freiburg, Freiburg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Fribourg-en-Brisgau</region><settlement type="city">Fribourg-en-Brisgau</settlement></placeName></affiliation></author></analytic><series><title level="j">PLoS Pathogens</title><idno type="ISSN">1553-7366</idno><idno type="eISSN">1553-7374</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The interferon-induced dynamin-like MxA GTPase restricts the replication of influenza A viruses. We identified adaptive mutations in the nucleoprotein (NP) of pandemic strains A/Brevig Mission/1/1918 (1918) and A/Hamburg/4/2009 (pH1N1) that confer MxA resistance. These resistance-associated amino acids in NP differ between the two strains but form a similar discrete surface-exposed cluster in the body domain of NP, indicating that MxA resistance evolved independently. The 1918 cluster was conserved in all descendent strains of seasonal influenza viruses. Introduction of this cluster into the NP of the MxA-sensitive influenza virus A/Thailand/1(KAN-1)/04 (H5N1) resulted in a gain of MxA resistance coupled with a decrease in viral replication fitness. Conversely, introduction of MxA-sensitive amino acids into pH1N1 NP enhanced viral growth in Mx-negative cells. We conclude that human MxA represents a barrier against zoonotic introduction of avian influenza viruses and that adaptive mutations in the viral NP should be carefully monitored.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Fouchier, Ra" uniqKey="Fouchier R">RA Fouchier</name></author><author><name sortKey="Schneeberger, Pm" uniqKey="Schneeberger P">PM Schneeberger</name></author><author><name sortKey="Rozendaal, Fw" uniqKey="Rozendaal F">FW Rozendaal</name></author><author><name sortKey="Broekman, Jm" uniqKey="Broekman J">JM Broekman</name></author><author><name sortKey="Kemink, Sa" uniqKey="Kemink S">SA Kemink</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tweed, Sa" uniqKey="Tweed S">SA Tweed</name></author><author><name sortKey="Skowronski, Dm" uniqKey="Skowronski D">DM Skowronski</name></author><author><name sortKey="David, St" uniqKey="David S">ST David</name></author><author><name 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<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">23555271</article-id><article-id pub-id-type="pmc">3610643</article-id><article-id pub-id-type="publisher-id">PPATHOGENS-D-12-02051</article-id><article-id pub-id-type="doi">10.1371/journal.ppat.1003279</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Biology</subject><subj-group><subject>Microbiology</subject><subj-group><subject>Immunity</subject><subj-group><subject>Innate Immunity</subject></subj-group></subj-group><subj-group><subject>Virology</subject><subj-group><subject>Viral Evolution</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Medicine</subject><subj-group><subject>Infectious Diseases</subject><subj-group><subject>Viral Diseases</subject></subj-group></subj-group></subj-group></article-categories><title-group><article-title>Pandemic Influenza A Viruses Escape from Restriction by Human MxA through Adaptive Mutations in the Nucleoprotein</article-title><alt-title alt-title-type="running-head">Molecular Determinants of MxA Resistance</alt-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Mänz</surname><given-names>Benjamin</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>¤</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Dornfeld</surname><given-names>Dominik</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Götz</surname><given-names>Veronika</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zell</surname><given-names>Roland</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zimmermann</surname><given-names>Petra</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Haller</surname><given-names>Otto</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kochs</surname><given-names>Georg</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schwemmle</surname><given-names>Martin</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>Department of Virology, Institute for Medical Microbiology and Hygiene, University of Freiburg, Freiburg, Germany</addr-line></aff><aff id="aff2"><label>2</label><addr-line>Institute of Virology und Antiviral Therapy, Universitätsklinikum Jena, Friedrich Schiller University Jena, Jena, Germany</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Ortin</surname><given-names>Juan</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>Centro Nacional de Biotecnologia (CSIC) and CIBER de Enfermedades Respiratorias, Spain</addr-line></aff><author-notes><corresp id="cor1">* E-mail: <email>georg.kochs@uniklinik-freiburg.de</email> (GK); <email>martin.schwemmle@uniklinik-freiburg.de</email> (MS)</corresp><fn fn-type="COI-statement"><p>The authors have declared that no competing interests exist.</p></fn><fn fn-type="con"><p>Conceived and designed the experiments: MS BM GK. Performed the experiments: MS BM DD VG PZ RZ. Analyzed the data: MS GK BM DD OH RZ. Wrote the paper: MS GK BM OH.</p></fn><fn id="fn1" fn-type="current-aff"><label>¤</label><p>Current address: Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.</p></fn></author-notes><pub-date pub-type="collection"><month>3</month><year>2013</year></pub-date><pub-date pub-type="epub"><day>28</day><month>3</month><year>2013</year></pub-date><volume>9</volume><issue>3</issue><elocation-id>e1003279</elocation-id><history><date date-type="received"><day>24</day><month>8</month><year>2012</year></date><date date-type="accepted"><day>13</day><month>2</month><year>2013</year></date></history><permissions><copyright-statement>© 2013 Mänz et al</copyright-statement><copyright-year>2013</copyright-year><copyright-holder>Mänz et al</copyright-holder><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>The interferon-induced dynamin-like MxA GTPase restricts the replication of influenza A viruses. We identified adaptive mutations in the nucleoprotein (NP) of pandemic strains A/Brevig Mission/1/1918 (1918) and A/Hamburg/4/2009 (pH1N1) that confer MxA resistance. These resistance-associated amino acids in NP differ between the two strains but form a similar discrete surface-exposed cluster in the body domain of NP, indicating that MxA resistance evolved independently. The 1918 cluster was conserved in all descendent strains of seasonal influenza viruses. Introduction of this cluster into the NP of the MxA-sensitive influenza virus A/Thailand/1(KAN-1)/04 (H5N1) resulted in a gain of MxA resistance coupled with a decrease in viral replication fitness. Conversely, introduction of MxA-sensitive amino acids into pH1N1 NP enhanced viral growth in Mx-negative cells. We conclude that human MxA represents a barrier against zoonotic introduction of avian influenza viruses and that adaptive mutations in the viral NP should be carefully monitored.</p></abstract><abstract abstract-type="summary"><title>Author Summary</title><p>Influenza A viruses of avian or swine origin sporadically enter into the human population but do not transmit between individuals. In rare cases, however, they establish a new virus lineage in humans. The mechanisms by which invading viruses overcome the species barrier are not well understood, but multiple adaptations to the new host are required. Surprisingly little is known about adaptive mutations that overcome restriction factors of the intrinsic and innate host defense system. In this study, we have identified adaptive mutations in pandemic strains A/Brevig Mission/1/1918 and A/Hamburg/4/2009 that confer resistance to the interferon-induced antiviral factor MxA which is a dynamin-like large GTPase that recognizes the incoming viral nucleocapsids and blocks their function. The resistance-enhancing mutations changed several amino acids in the viral nucleoprotein which is the main nucleocapsid component. These mutations were sufficient to increase the pathogenicity of an avian influenza virus strain in a Mx-positive mouse model. Interestingly, the resistance-associated amino acids are counter-selected in circulating avian influenza strains, because they compromise general viral replication fitness. The present data indicate that the innate immunity factor MxA provides a barrier against zoonotic introduction of influenza A viruses and that adaptive mutations in the nucleoprotein must be carefully monitored.</p></abstract><funding-group><funding-statement>This work was supported by the Deutsche Forschungsgemeinschaft, grant Ko 1579/8-1 to GK and the Bundesministerium für Bildung und Forschung (FluResearchNet) to MS and RZ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement></funding-group><counts><page-count count="16"></page-count></counts></article-meta></front></pmc><affiliations><list><country><li>Allemagne</li></country><region><li>Bade-Wurtemberg</li><li>District de Fribourg-en-Brisgau</li></region><settlement><li>Fribourg-en-Brisgau</li></settlement></list><tree><country name="Allemagne"><region name="Bade-Wurtemberg"><name sortKey="M Nz, Benjamin" sort="M Nz, Benjamin" uniqKey="M Nz B" first="Benjamin" last="M Nz">Benjamin M Nz</name></region><name sortKey="Dornfeld, Dominik" sort="Dornfeld, Dominik" uniqKey="Dornfeld D" first="Dominik" last="Dornfeld">Dominik Dornfeld</name><name sortKey="Gotz, Veronika" sort="Gotz, Veronika" uniqKey="Gotz V" first="Veronika" last="Götz">Veronika Götz</name><name sortKey="Haller, Otto" sort="Haller, Otto" uniqKey="Haller O" first="Otto" last="Haller">Otto Haller</name><name sortKey="Kochs, Georg" sort="Kochs, Georg" uniqKey="Kochs G" first="Georg" last="Kochs">Georg Kochs</name><name sortKey="Schwemmle, Martin" sort="Schwemmle, Martin" uniqKey="Schwemmle M" first="Martin" last="Schwemmle">Martin Schwemmle</name><name sortKey="Zell, Roland" sort="Zell, Roland" uniqKey="Zell R" first="Roland" last="Zell">Roland Zell</name><name sortKey="Zimmermann, Petra" sort="Zimmermann, Petra" uniqKey="Zimmermann P" first="Petra" last="Zimmermann">Petra Zimmermann</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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