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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The Virulence of 1997 H5N1 Influenza Viruses in the Mouse Model Is Increased by Correcting a Defect in Their NS1 Proteins
<xref ref-type="fn" rid="FN2"><sup>▿</sup></xref></title><author><name sortKey="Spesock, April" sort="Spesock, April" uniqKey="Spesock A" first="April" last="Spesock">April Spesock</name><affiliation><nlm:aff id="aff1">Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia 30333</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Battelle, Atlanta, Georgia 30333</nlm:aff></affiliation></author><author><name sortKey="Malur, Meghana" sort="Malur, Meghana" uniqKey="Malur M" first="Meghana" last="Malur">Meghana Malur</name><affiliation><nlm:aff id="aff2">Department of Molecular Genetics and Microbiology, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas 78712</nlm:aff></affiliation></author><author><name sortKey="Hossain, M Jaber" sort="Hossain, M Jaber" uniqKey="Hossain M" first="M. Jaber" last="Hossain">M. Jaber Hossain</name><affiliation><nlm:aff id="aff1">Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia 30333</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Battelle, Atlanta, Georgia 30333</nlm:aff></affiliation></author><author><name sortKey="Chen, Li Mei" sort="Chen, Li Mei" uniqKey="Chen L" first="Li-Mei" last="Chen">Li-Mei Chen</name><affiliation><nlm:aff id="aff1">Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia 30333</nlm:aff></affiliation></author><author><name sortKey="Njaa, Bradley L" sort="Njaa, Bradley L" uniqKey="Njaa B" first="Bradley L." last="Njaa">Bradley L. Njaa</name><affiliation><nlm:aff id="aff3">Department of Pathobiology, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, Oklahoma 74078</nlm:aff></affiliation></author><author><name sortKey="Davis, Charles T" sort="Davis, Charles T" uniqKey="Davis C" first="Charles T." last="Davis">Charles T. Davis</name><affiliation><nlm:aff id="aff1">Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia 30333</nlm:aff></affiliation></author><author><name sortKey="Lipatov, Aleksandr S" sort="Lipatov, Aleksandr S" uniqKey="Lipatov A" first="Aleksandr S." last="Lipatov">Aleksandr S. Lipatov</name><affiliation><nlm:aff id="aff1">Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia 30333</nlm:aff></affiliation></author><author><name sortKey="York, Ian A" sort="York, Ian A" uniqKey="York I" first="Ian A." last="York">Ian A. York</name><affiliation><nlm:aff id="aff1">Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia 30333</nlm:aff></affiliation></author><author><name sortKey="Krug, Robert M" sort="Krug, Robert M" uniqKey="Krug R" first="Robert M." last="Krug">Robert M. Krug</name><affiliation><nlm:aff id="aff2">Department of Molecular Genetics and Microbiology, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas 78712</nlm:aff></affiliation></author><author><name sortKey="Donis, Ruben O" sort="Donis, Ruben O" uniqKey="Donis R" first="Ruben O." last="Donis">Ruben O. Donis</name><affiliation><nlm:aff id="aff1">Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia 30333</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">21593152</idno><idno type="pmc">3126612</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3126612</idno><idno type="RBID">PMC:3126612</idno><idno type="doi">10.1128/JVI.00417-11</idno><date when="2011">2011</date><idno type="wicri:Area/Pmc/Corpus">000638</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000638</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The Virulence of 1997 H5N1 Influenza Viruses in the Mouse Model Is Increased by Correcting a Defect in Their NS1 Proteins
<xref ref-type="fn" rid="FN2"><sup>▿</sup></xref></title><author><name sortKey="Spesock, April" sort="Spesock, April" uniqKey="Spesock A" first="April" last="Spesock">April Spesock</name><affiliation><nlm:aff id="aff1">Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia 30333</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Battelle, Atlanta, Georgia 30333</nlm:aff></affiliation></author><author><name sortKey="Malur, Meghana" sort="Malur, Meghana" uniqKey="Malur M" first="Meghana" last="Malur">Meghana Malur</name><affiliation><nlm:aff id="aff2">Department of Molecular Genetics and Microbiology, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas 78712</nlm:aff></affiliation></author><author><name sortKey="Hossain, M Jaber" sort="Hossain, M Jaber" uniqKey="Hossain M" first="M. Jaber" last="Hossain">M. Jaber Hossain</name><affiliation><nlm:aff id="aff1">Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia 30333</nlm:aff></affiliation><affiliation><nlm:aff id="aff4">Battelle, Atlanta, Georgia 30333</nlm:aff></affiliation></author><author><name sortKey="Chen, Li Mei" sort="Chen, Li Mei" uniqKey="Chen L" first="Li-Mei" last="Chen">Li-Mei Chen</name><affiliation><nlm:aff id="aff1">Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia 30333</nlm:aff></affiliation></author><author><name sortKey="Njaa, Bradley L" sort="Njaa, Bradley L" uniqKey="Njaa B" first="Bradley L." last="Njaa">Bradley L. Njaa</name><affiliation><nlm:aff id="aff3">Department of Pathobiology, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, Oklahoma 74078</nlm:aff></affiliation></author><author><name sortKey="Davis, Charles T" sort="Davis, Charles T" uniqKey="Davis C" first="Charles T." last="Davis">Charles T. Davis</name><affiliation><nlm:aff id="aff1">Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia 30333</nlm:aff></affiliation></author><author><name sortKey="Lipatov, Aleksandr S" sort="Lipatov, Aleksandr S" uniqKey="Lipatov A" first="Aleksandr S." last="Lipatov">Aleksandr S. Lipatov</name><affiliation><nlm:aff id="aff1">Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia 30333</nlm:aff></affiliation></author><author><name sortKey="York, Ian A" sort="York, Ian A" uniqKey="York I" first="Ian A." last="York">Ian A. York</name><affiliation><nlm:aff id="aff1">Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia 30333</nlm:aff></affiliation></author><author><name sortKey="Krug, Robert M" sort="Krug, Robert M" uniqKey="Krug R" first="Robert M." last="Krug">Robert M. Krug</name><affiliation><nlm:aff id="aff2">Department of Molecular Genetics and Microbiology, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas 78712</nlm:aff></affiliation></author><author><name sortKey="Donis, Ruben O" sort="Donis, Ruben O" uniqKey="Donis R" first="Ruben O." last="Donis">Ruben O. Donis</name><affiliation><nlm:aff id="aff1">Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia 30333</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="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The NS1 protein of human influenza A viruses binds the 30-kDa subunit of the cleavage and polyadenylation specificity factor (CPSF30), a protein required for 3′ end processing of cellular pre-mRNAs, thereby inhibiting production of beta interferon (IFN-β) mRNA. The NS1 proteins of pathogenic 1997 H5N1 viruses contain the CPSF30-binding site but lack the consensus amino acids at positions 103 and 106, F and M, respectively, that are required for the stabilization of CPSF30 binding, resulting in nonoptimal CPSF30 binding in infected cells. Here we have demonstrated that strengthening CPSF30 binding, by changing positions 103 and 106 in the 1997 H5N1 NS1 protein to the consensus amino acids, results in a remarkable 300-fold increase in the lethality of the virus in mice. Unexpectedly, this increase in virulence is not associated with increased lung pathology but rather is characterized by faster systemic spread of the virus, particularly to the brain, where increased replication and severe pathology occur. This increased spread is associated with increased cytokine and chemokine levels in extrapulmonary tissues. We conclude that strengthening CPSF30 binding by the NS1 protein of 1997 H5N1 viruses enhances virulence in mice by increasing the systemic spread of the virus from the lungs, particularly to the brain.</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="hwp">jvi</journal-id><journal-id journal-id-type="pmc">jvi</journal-id><journal-id journal-id-type="publisher-id">JVI</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</publisher-name><publisher-loc>1752 N St., N.W., Washington, DC</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">21593152</article-id><article-id pub-id-type="pmc">3126612</article-id><article-id pub-id-type="publisher-id">0417-11</article-id><article-id pub-id-type="doi">10.1128/JVI.00417-11</article-id><article-categories><subj-group subj-group-type="heading"><subject>Pathogenesis and Immunity</subject></subj-group></article-categories><title-group><article-title>The Virulence of 1997 H5N1 Influenza Viruses in the Mouse Model Is Increased by Correcting a Defect in Their NS1 Proteins
<xref ref-type="fn" rid="FN2"><sup>▿</sup></xref></article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Spesock</surname><given-names>April</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff4"><sup>4</sup></xref><xref ref-type="author-notes" rid="FN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Malur</surname><given-names>Meghana</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="author-notes" rid="FN1">†</xref></contrib><contrib contrib-type="author"><name><surname>Hossain</surname><given-names>M. Jaber</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Li-Mei</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Njaa</surname><given-names>Bradley L.</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Davis</surname><given-names>Charles T.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lipatov</surname><given-names>Aleksandr S.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>York</surname><given-names>Ian A.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Krug</surname><given-names>Robert M.</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="corresp" rid="cor1">*</xref></contrib><contrib contrib-type="author"><name><surname>Donis</surname><given-names>Ruben O.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="corresp" rid="cor1">*</xref></contrib><aff id="aff1"><label>1</label>Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia 30333</aff><aff id="aff2"><label>2</label>Department of Molecular Genetics and Microbiology, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin, Texas 78712</aff><aff id="aff3"><label>3</label>Department of Pathobiology, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, Oklahoma 74078</aff><aff id="aff4"><label>4</label>Battelle, Atlanta, Georgia 30333</aff></contrib-group><author-notes><corresp id="cor1"><label>*</label>Corresponding author. Mailing address for Ruben O. Donis: <addr-line>Centers for Disease Control and Prevention, Influenza Division, 1600 Clifton Road NE, MD G16, Atlanta, GA 30333</addr-line>. Phone: <phone>(404) 639-4968</phone>. Fax: <fax>(404) 639-2350</fax>. E-mail: <email>rvd6@cdc.gov</email>. Mailing address for Robert M. Krug: <addr-line>Institute for Cellular and Molecular Biology, Section of Molecular Genetics and Microbiology, 2500 Speedway, MBB 2. 122, University of Texas at Austin, Austin, TX 78712</addr-line>. Phone: <phone>(512) 232-5564</phone>. Fax: <fax>(512) 232-5565</fax>. E-mail: <email>rkrug@mail.utexas.edu</email>.</corresp><fn id="FN1" fn-type="equal"><label>†</label><p>These authors contributed equally to this research.</p></fn></author-notes><pub-date pub-type="ppub"><month>7</month><year>2011</year></pub-date><volume>85</volume><issue>14</issue><fpage>7048</fpage><lpage>7058</lpage><history><date date-type="received"><day>2</day><month>3</month><year>2011</year></date><date date-type="accepted"><day>26</day><month>4</month><year>2011</year></date></history><permissions><copyright-statement>Copyright © 2011, American Society for Microbiology</copyright-statement><copyright-year>2011</copyright-year><copyright-holder>American Society for Microbiology</copyright-holder></permissions><self-uri xlink:title="pdf" xlink:type="simple" xlink:href="zjv01411007048.pdf"></self-uri><abstract><p>The NS1 protein of human influenza A viruses binds the 30-kDa subunit of the cleavage and polyadenylation specificity factor (CPSF30), a protein required for 3′ end processing of cellular pre-mRNAs, thereby inhibiting production of beta interferon (IFN-β) mRNA. The NS1 proteins of pathogenic 1997 H5N1 viruses contain the CPSF30-binding site but lack the consensus amino acids at positions 103 and 106, F and M, respectively, that are required for the stabilization of CPSF30 binding, resulting in nonoptimal CPSF30 binding in infected cells. Here we have demonstrated that strengthening CPSF30 binding, by changing positions 103 and 106 in the 1997 H5N1 NS1 protein to the consensus amino acids, results in a remarkable 300-fold increase in the lethality of the virus in mice. Unexpectedly, this increase in virulence is not associated with increased lung pathology but rather is characterized by faster systemic spread of the virus, particularly to the brain, where increased replication and severe pathology occur. This increased spread is associated with increased cytokine and chemokine levels in extrapulmonary tissues. We conclude that strengthening CPSF30 binding by the NS1 protein of 1997 H5N1 viruses enhances virulence in mice by increasing the systemic spread of the virus from the lungs, particularly to the brain.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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