Inefficient Control of Host Gene Expression by the 2009 Pandemic H1N1 Influenza A Virus NS1 Protein
Benjamin G. Hale,John Steel,Rafael A. Medina,Balaji Manicassamy,Jianqiang Ye,Danielle Hickman,Rong Hai,Mirco Schmolke,Anice C. Lowen,Daniel R. Perez,Adolfo García-Sastre +10 more
TL;DR: Although the 2009 H1N1 virus NS1 protein (2009/NS1) is an effective interferon antagonist, it is found that this NS1 (unlike those of previous human-adapted influenza A viruses) is unable to block general host gene expression in human or swine cells.
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Abstract: In 2009, a novel swine-origin H1N1 influenza A virus emerged. Here, we characterize the multifunctional NS1 protein of this human pandemic virus in order to understand factors that may contribute to replication efficiency or pathogenicity. Although the 2009 H1N1 virus NS1 protein (2009/NS1) is an effective interferon antagonist, we found that this NS1 (unlike those of previous human-adapted influenza A viruses) is unable to block general host gene expression in human or swine cells. This property could be restored in 2009/NS1 by replacing R108, E125, and G189 with residues corresponding to human virus consensus. Mechanistically, these previously undescribed mutations acted by increasing binding of 2009/NS1 to the cellular pre-mRNA processing protein CPSF30. A recombinant 2009 H1N1 influenza A virus (A/California/04/09) expressing NS1 with these gain-of-function substitutions was more efficient than the wild type at antagonizing host innate immune responses in primary human epithelial cells. However, such mutations had no significant effect on virus replication in either human or swine tissue culture substrates. Surprisingly, in a mouse model of pathogenicity, the mutant virus appeared to cause less morbidity, and was cleared faster, than the wild type. The mutant virus also demonstrated reduced titers in the upper respiratory tracts of ferrets; however, contact and aerosol transmissibility of the virus was unaffected. Our data highlight a potential human adaptation of NS1 that seems absent in "classically derived" swine-origin influenza A viruses, including the 2009 H1N1 virus. We discuss the impact that a natural future gain of this NS1 function may have on the new pandemic virus in humans.
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References
Large-Scale Sequence Analysis of Avian Influenza Isolates
John C. Obenauer,Jackie Denson,Perdeep K. Mehta,Xiaoping Su,Suraj Mukatira,David B. Finkelstein,Xiequn Xu,Jinhua Wang,Jing Ma,Yiping Fan,Karen M. Rakestraw,Robert G. Webster,Robert G. Webster,Erich Hoffmann,Scott Krauss,Jie Zheng,Ziwei Zhang,Clayton W. Naeve,Clayton W. Naeve +18 more
TL;DR: A preliminary analysis of the first large-scale sequencing of AIVs, including 2196 AIV genes and 169 complete genomes, is reported here to identify new gene alleles, persistent genotypes, compensatory mutations, and a potential virulence determinant.
Sequence of the 1918 pandemic influenza virus nonstructural gene (NS) segment and characterization of recombinant viruses bearing the 1918 NS genes
Christopher F. Basler,Ann H. Reid,Jody K. Dybing,Thomas A. Janczewski,Thomas G. Fanning,Hongyong Zheng,Mirella Salvatore,Michael L. Perdue,David E. Swayne,Adolfo García-Sastre,Peter Palese,Jeffery K. Taubenberger +11 more
TL;DR: The sequence of the A/Brevig Mission/1/18 (H1N1) virus nonstructural (NS) segment encoding two proteins, NS1 and nuclear export protein is reported, suggesting that interaction of the NS1 protein with host-cell factors plays a significant role in viral pathogenesis.
Polyclonal and monoclonal antibodies to the interferon-inducible protein Mx of influenza virus-resistant mice.
TL;DR: Synthesis of the immunoprecipitable 75,000-dalton protein Mx was induced by interferon-alpha/beta but not by interFERon-gamma in Mx+ cells of diverse genetic backgrounds, and one discrete in vitro translation product of relevant mRNA reacted with polyclonal and monoclonal antibodies and was indistinguishable from in vivo synthesizedprotein Mx.
A unique cap(m7GpppXm)-dependent influenza virion endonuclease cleaves capped RNAs to generate the primers that initiate viral RNA transcription
TL;DR: It is shown that virions and purified viral cores contain a unique endonuclease that cleaves RNAs containing a 5' methylated cap structure preferentially at purine residues 10 to 14 nucleotides from the cap, generating fragments with 3'-terminal hydroxyl groups.
RIG-I-Mediated Antiviral Responses to Single-Stranded RNA Bearing 5' Phosphates
Andreas Pichlmair,Oliver Schulz,Choon Ping Tan,Tanja I. Näslund,Peter Liljeström,Friedemann Weber,Caetano Reis e Sousa +6 more
TL;DR: It is shown that influenza A virus infection does not generate dsRNA and that RIG-I is activated by viral genomic single-stranded RNA (ssRNA) bearing 5′-phosphates, and suggested that its ability to sense 5'-phosphorylated RNA evolved in the innate immune system as a means of discriminating between self and nonself.
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