title: Influenza A virus abrogates IFN-gamma response in respiratory epithelial cells by disruption of the Jak/Stat pathway.
abstract: The innate immunity to viral infections induces a potent antiviral response mediated by interferons (IFN). Although IFN-gamma is detected during the acute stages of illness in the upper respiratory tract secretions and in the serum of influenza A virus-infected individuals, control of influenza A virus is not dependent upon IFN-gamma as evidenced by studies using anti-IFN-gamma Ab and IFN-gamma(-/-) mice. Thus, we hypothesized that IFN-gamma is not critical in host survival because influenza A virus has mechanisms to evade the antiviral activity of IFN-gamma. To test this, A549 cells, an epithelial cell line derived from lung adenocarcinoma, were infected with influenza virus strain A/Aichi/2/68 (H3N2) (Aichi) and/or stimulated with IFN-gamma to detect IFN-gamma-stimulated MHC class II expression. Influenza A virus infection inhibited IFN-gamma-induced up-regulation of HLA-DRalpha mRNA and the IFN-gamma induction of class II transactivator (CIITA), an obligate mediator of MHC class II expression. Nuclear translocation of Stat1alpha upon IFN-gamma stimulation was significantly inhibited in influenza A virus-infected cells and this was associated with a decrease in Tyr701 and Ser727 phosphorylation of Stat1alpha. Thus, influenza A virus subverts antiviral host defense mediated by IFN-gamma through effects on the intracellular signaling pathways.
authors.affiliation: Department of Hygiene, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan. uetanik@wakayama-med.ac.jp
authors.forename: Kohsaku
authors.initials: K
authors.lastname: Uetani
authors.forename: Miki
authors.initials: M
authors.lastname: Hiroi
authors.forename: Tadamichi
authors.initials: T
authors.lastname: Meguro
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ogawa
authors.forename: Toshinori
authors.initials: T
authors.lastname: Kamisako
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ohmori
authors.forename: Serpil C
authors.initials: SC
authors.lastname: Erzurum
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000821:virology*; D019204:GTP-Binding Proteins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006684:HLA-DR Antigens / Q000235:genetics; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics; D009980:Influenza A virus / Q000276:immunology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D050856:Interferon Regulatory Factor-1 / Q000235:genetics; D050832:Interferon-Stimulated Gene Factor 3 / Q000378:metabolism; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism*; D018613:Microscopy, Confocal; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000096743:Interferon gamma Receptor
chemical_list: D019204:GTP-Binding Proteins; D006684:HLA-DR Antigens; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D018799:Intercellular Adhesion Molecule-1; D050856:Interferon Regulatory Factor-1; D050832:Interferon-Stimulated Gene Factor 3; D016898:Interferon-alpha; D007371:Interferon-gamma; D053613:Janus Kinase 1; D016328:NF-kappa B; D009687:Nuclear Proteins; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D000096743:Interferon gamma Receptor; C490287:GBP1 protein, human; C083728:MHC class II transactivator protein; C494079:STAT1 protein, human; C079868:gamma interferon activation factor; C507904:JAK1 protein, human