title: The NS1 protein of the 1918 pandemic influenza virus blocks host interferon and lipid metabolism pathways.
abstract: The "Spanish influenza" of 1918 claimed an unprecedented number of lives, yet the determinants of virulence for this virus are still not fully understood. Here, we used functional genomics and an in vitro human lung epithelial cell infection model to define the global host transcriptional response to the eight-gene 1918 virus. To better understand the role of the 1918 virus NS1 gene, we also evaluated the host response to a reassortant 1918 virus containing the NS1 gene from A/Texas/36/91 (a seasonal isolate of human influenza virus), as well as the host response to a reassortant of A/Texas/36/91 containing the 1918 NS1 gene. Genomic analyses revealed that the 1918 virus blocked the transcription of multiple interferon-stimulated genes and also downregulated a network of genes associated with lipid metabolism. In contrast, the expression of genes encoding chemokines and cytokines, which serve to attract infiltrating immune cells, was upregulated. Viruses containing the NS1 gene from A/Texas/36/91 induced a significant increase in type I interferon signaling but did not repress lipid metabolism. The 1918 NS1 gene may therefore have contributed to the virulence of the 1918 pandemic virus by disrupting the innate immune response, inducing hypercytokinemia, and by blocking the transcription of certain lipid-based proinflammatory mediators that function as part of the host antiviral response.
authors.affiliation: Department of Microbiology and Washington National Primate Research Center, University of Washington, Seattle, WA 98195-8070, USA.
authors.forename: Rosalind
authors.initials: R
authors.lastname: Billharz
authors.forename: Hui
authors.initials: H
authors.lastname: Zeng
authors.forename: Sean C
authors.initials: SC
authors.lastname: Proll
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Korth
authors.forename: Sharon
authors.initials: S
authors.lastname: Lederer
authors.forename: Randy
authors.initials: R
authors.lastname: Albrecht
authors.forename: Alan G
authors.initials: AG
authors.lastname: Goodman
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rosenzweig
authors.forename: Terrence M
authors.initials: TM
authors.lastname: Tumpey
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.forename: Michael G
authors.initials: MG
authors.lastname: Katze
mesh_terms: D002460:Cell Line; D004196:Disease Outbreaks; D004847:Epithelial Cells / Q000166:cytology / Q000821:virology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity; D007251:Influenza, Human / Q000453:epidemiology / Q000276:immunology / Q000821:virology; D007372:Interferons / Q000187:drug effects* / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D008168:Lung / Q000166:cytology / Q000821:virology*; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D010948:Viral Plaque Assay
chemical_list: C085820:INS1 protein, influenza virus; D011506:Proteins; D011993:Recombinant Fusion Proteins; D017361:Viral Nonstructural Proteins; D007372:Interferons
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