title: An overlapping protein-coding region in influenza A virus segment 3 modulates the host response.
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.
authors: Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK.
authors: B W
authors: BW
authors: Jagger
authors: H M
authors: HM
authors: Wise
authors: J C
authors: JC
authors: Kash
authors: K-A
authors: KA
authors: Walters
authors: N M
authors: NM
authors: Wills
authors: Y-L
authors: YL
authors: Xiao
authors: R L
authors: RL
authors: Dunfee
authors: L M
authors: LM
authors: Schwartzman
authors: A
authors: A
authors: Ozinsky
authors: G L
authors: GL
authors: Bell
authors: R M
authors: RM
authors: Dalton
authors: A
authors: A
authors: Lo
authors: S
authors: S
authors: Efstathiou
authors: J F
authors: JF
authors: Atkins
authors: A E
authors: AE
authors: Firth
authors: J K
authors: JK
authors: Taubenberger
authors: P
authors: P
authors: Digard
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D003062:Codon; D017124:Conserved Sequence; D005260:Female; D018965:Frameshifting, Ribosomal; D005786:Gene Expression Regulation; D016679:Genome, Viral; D057809:HEK293 Cells; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics* / Q000254:growth & development / Q000472:pathogenicity; D009980:Influenza A virus / Q000235:genetics* / Q000378:metabolism; D008168:Lung / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009154:Mutation; D016366:Open Reading Frames; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000821:virology*; D054730:Protein Interaction Domains and Motifs; D020543:Proteome; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D016865:Reassortant Viruses / Q000235:genetics; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D014764:Viral Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D003062:Codon; C061290:PA protein, influenza viruses; C573926:PA-X protein, influenza A virus; D020543:Proteome; D012333:RNA, Messenger; D012367:RNA, Viral; D012097:Repressor Proteins; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; D012324:RNA-Dependent RNA Polymerase