title: Respiratory virus-induced EGFR activation suppresses IRF1-dependent interferon λ and antiviral defense in airway epithelium.
abstract: Viruses suppress host responses to increase infection, and understanding these mechanisms has provided insights into cellular signaling and led to novel therapies. Many viruses (e.g., Influenza virus, Rhinovirus [RV], Cytomegalovirus, Epstein-Barr virus, and Hepatitis C virus) activate epithelial epidermal growth factor receptor (EGFR), a tyrosine kinase receptor, but the role of EGFR in viral pathogenesis is not clear. Interferon (IFN) signaling is a critical innate antiviral host response and recent experiments have implicated IFN-λ, a type III IFN, as the most significant IFN for mucosal antiviral immune responses. Despite the importance of IFN-λ in epithelial antiviral responses, the role and mechanisms of epithelial IFN-λ signaling have not been fully elucidated. We report that respiratory virus-induced EGFR activation suppresses endogenous airway epithelial antiviral signaling. We found that Influenza virus- and RV-induced EGFR activation suppressed IFN regulatory factor (IRF) 1-induced IFN-λ production and increased viral infection. In addition, inhibition of EGFR during viral infection augmented IRF1 and IFN-λ, which resulted in decreased viral titers in vitro and in vivo. These findings describe a novel mechanism that viruses use to suppress endogenous antiviral defenses, and provide potential targets for future therapies.
authors.affiliation: Department of Medicine, 2 Cardiovascular Research Institute, 3 Department of Microbiology and Immunology, and 4 Cancer Research Institute, University of California, San Francisco, San Francisco, CA 94122.
authors.forename: Iris F
authors.initials: IF
authors.lastname: Ueki
authors.forename: Gundula
authors.initials: G
authors.lastname: Min-Oo
authors.forename: April
authors.initials: A
authors.lastname: Kalinowski
authors.forename: Eric
authors.initials: E
authors.lastname: Ballon-Landa
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Lanier
authors.forename: Jay A
authors.initials: JA
authors.lastname: Nadel
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Koff
mesh_terms: D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D014777:Virus Diseases / Q000276:immunology / Q000378:metabolism; D053586:Virus Internalization
chemical_list: D050856:Interferon Regulatory Factor-1; D047428:Protein Kinase Inhibitors; D007371:Interferon-gamma; D066246:ErbB Receptors