The Virulence of 1997 H5N1 Influenza Viruses in the Mouse Model Is Increased by Correcting a Defect in Their NS1 Proteins ▿
Identifieur interne : 000C06 ( Main/Exploration ); précédent : 000C05; suivant : 000C07The Virulence of 1997 H5N1 Influenza Viruses in the Mouse Model Is Increased by Correcting a Defect in Their NS1 Proteins ▿
Auteurs : April Spesock [États-Unis] ; Meghana Malur [États-Unis] ; M. Jaber Hossain [États-Unis] ; Li-Mei Chen [États-Unis] ; Bradley L. Njaa [États-Unis] ; Charles T. Davis [États-Unis] ; Aleksandr S. Lipatov [États-Unis] ; Ian A. York [États-Unis] ; Robert M. Krug [États-Unis] ; Ruben O. Donis [États-Unis]Source :
- Journal of Virology [ 0022-538X ] ; 2011.
Abstract
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.
Url:
DOI: 10.1128/JVI.00417-11
PubMed: 21593152
PubMed Central: 3126612
Affiliations:
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<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 wicri:level="2"><nlm:aff id="aff1">Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia 30333</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Géorgie (États-Unis)</region></placeName><wicri:cityArea>Influenza Division, Centers for Disease Control and Prevention, Atlanta</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="aff4">Battelle, Atlanta, Georgia 30333</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Géorgie (États-Unis)</region></placeName><wicri:cityArea>Battelle, Atlanta</wicri:cityArea></affiliation></author><author><name sortKey="Malur, Meghana" sort="Malur, Meghana" uniqKey="Malur M" first="Meghana" last="Malur">Meghana Malur</name><affiliation wicri:level="2"><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><country xml:lang="fr">États-Unis</country><placeName><region type="state">Texas</region></placeName><wicri:cityArea>Department of Molecular Genetics and Microbiology, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin</wicri:cityArea></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 wicri:level="2"><nlm:aff id="aff1">Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia 30333</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Géorgie (États-Unis)</region></placeName><wicri:cityArea>Influenza Division, Centers for Disease Control and Prevention, Atlanta</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="aff4">Battelle, Atlanta, Georgia 30333</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Géorgie (États-Unis)</region></placeName><wicri:cityArea>Battelle, Atlanta</wicri:cityArea></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 wicri:level="2"><nlm:aff id="aff1">Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia 30333</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Géorgie (États-Unis)</region></placeName><wicri:cityArea>Influenza Division, Centers for Disease Control and Prevention, Atlanta</wicri:cityArea></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 wicri:level="2"><nlm:aff id="aff3">Department of Pathobiology, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, Oklahoma 74078</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Oklahoma</region></placeName><wicri:cityArea>Department of Pathobiology, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater</wicri:cityArea></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 wicri:level="2"><nlm:aff id="aff1">Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia 30333</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Géorgie (États-Unis)</region></placeName><wicri:cityArea>Influenza Division, Centers for Disease Control and Prevention, Atlanta</wicri:cityArea></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 wicri:level="2"><nlm:aff id="aff1">Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia 30333</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Géorgie (États-Unis)</region></placeName><wicri:cityArea>Influenza Division, Centers for Disease Control and Prevention, Atlanta</wicri:cityArea></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 wicri:level="2"><nlm:aff id="aff1">Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia 30333</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Géorgie (États-Unis)</region></placeName><wicri:cityArea>Influenza Division, Centers for Disease Control and Prevention, Atlanta</wicri:cityArea></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 wicri:level="2"><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><country xml:lang="fr">États-Unis</country><placeName><region type="state">Texas</region></placeName><wicri:cityArea>Department of Molecular Genetics and Microbiology, Institute for Cellular and Molecular Biology, University of Texas at Austin, Austin</wicri:cityArea></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 wicri:level="2"><nlm:aff id="aff1">Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia 30333</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Géorgie (États-Unis)</region></placeName><wicri:cityArea>Influenza Division, Centers for Disease Control and Prevention, Atlanta</wicri:cityArea></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><affiliations><list><country><li>États-Unis</li></country><region><li>Géorgie (États-Unis)</li><li>Oklahoma</li><li>Texas</li></region></list><tree><country name="États-Unis"><region name="Géorgie (États-Unis)"><name sortKey="Spesock, April" sort="Spesock, April" uniqKey="Spesock A" first="April" last="Spesock">April Spesock</name></region><name sortKey="Chen, Li Mei" sort="Chen, Li Mei" uniqKey="Chen L" first="Li-Mei" last="Chen">Li-Mei Chen</name><name sortKey="Davis, Charles T" sort="Davis, Charles T" uniqKey="Davis C" first="Charles T." last="Davis">Charles T. Davis</name><name sortKey="Donis, Ruben O" sort="Donis, Ruben O" uniqKey="Donis R" first="Ruben O." last="Donis">Ruben O. Donis</name><name sortKey="Hossain, M Jaber" sort="Hossain, M Jaber" uniqKey="Hossain M" first="M. Jaber" last="Hossain">M. Jaber Hossain</name><name sortKey="Hossain, M Jaber" sort="Hossain, M Jaber" uniqKey="Hossain M" first="M. Jaber" last="Hossain">M. Jaber Hossain</name><name sortKey="Krug, Robert M" sort="Krug, Robert M" uniqKey="Krug R" first="Robert M." last="Krug">Robert M. Krug</name><name sortKey="Lipatov, Aleksandr S" sort="Lipatov, Aleksandr S" uniqKey="Lipatov A" first="Aleksandr S." last="Lipatov">Aleksandr S. Lipatov</name><name sortKey="Malur, Meghana" sort="Malur, Meghana" uniqKey="Malur M" first="Meghana" last="Malur">Meghana Malur</name><name sortKey="Njaa, Bradley L" sort="Njaa, Bradley L" uniqKey="Njaa B" first="Bradley L." last="Njaa">Bradley L. Njaa</name><name sortKey="Spesock, April" sort="Spesock, April" uniqKey="Spesock A" first="April" last="Spesock">April Spesock</name><name sortKey="York, Ian A" sort="York, Ian A" uniqKey="York I" first="Ian A." last="York">Ian A. York</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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