Abstract
Influenza A virus (IAV) infection leads to variable and imperfectly understood pathogenicity. We report that segment 3 of the virus contains a second open reading frame ("X-ORF"), accessed via ribosomal frameshifting. The frameshift product, termed PA-X, comprises the endonuclease domain of the viral PA protein with a C-terminal domain encoded by the X-ORF and functions to repress cellular gene expression. PA-X also modulates IAV virulence in a mouse infection model, acting to decrease pathogenicity. Loss of PA-X expression leads to changes in the kinetics of the global host response, which notably includes increases in inflammatory, apoptotic, and T lymphocyte-signaling pathways. Thus, we have identified a previously unknown IAV protein that modulates the host response to infection, a finding with important implications for understanding IAV pathogenesis.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Base Sequence
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Cell Line
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Codon
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Conserved Sequence
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Female
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Frameshifting, Ribosomal*
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Gene Expression Regulation
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Genome, Viral
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HEK293 Cells
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Humans
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Influenza A Virus, H1N1 Subtype / genetics*
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Influenza A Virus, H1N1 Subtype / growth & development
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Influenza A Virus, H1N1 Subtype / pathogenicity
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Influenza A virus / genetics*
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Influenza A virus / metabolism
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Lung / pathology
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Lung / virology
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Mice
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Mice, Inbred BALB C
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Molecular Sequence Data
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Mutation
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Open Reading Frames*
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Orthomyxoviridae Infections / genetics
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Orthomyxoviridae Infections / immunology
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Orthomyxoviridae Infections / pathology
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Orthomyxoviridae Infections / virology*
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Protein Interaction Domains and Motifs
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Proteome
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Viral / genetics
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RNA, Viral / metabolism
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RNA-Dependent RNA Polymerase / chemistry
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RNA-Dependent RNA Polymerase / genetics*
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RNA-Dependent RNA Polymerase / metabolism*
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Reassortant Viruses / genetics
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Repressor Proteins / chemistry
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Repressor Proteins / genetics*
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Repressor Proteins / metabolism*
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Viral Nonstructural Proteins / chemistry
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Viral Nonstructural Proteins / genetics*
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Viral Nonstructural Proteins / metabolism*
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Viral Proteins / biosynthesis
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Viral Proteins / chemistry
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Viral Proteins / genetics*
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Viral Proteins / metabolism*
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Virus Replication
Substances
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Codon
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PA protein, influenza viruses
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PA-X protein, influenza A virus
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Proteome
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RNA, Messenger
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RNA, Viral
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Repressor Proteins
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Viral Nonstructural Proteins
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Viral Proteins
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RNA-Dependent RNA Polymerase