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Specific Inhibition of Type I Interferon Signal Transduction by Respiratory Syncytial Virus

Department of Internal Medicine, University of Iowa Roy J. and Lucille A. Carver College of Medicine, and Veterans Administration Medical Center, Iowa City, Iowa

Address correspondence to: Dwight C. Look, M.D., University of Iowa Roy J. and Lucille A. Carver College of Medicine, Department of Internal Medicine, 200 Hawkins Drive, C33-GH, Iowa City, IA 52242. E-mail: dwight-look{at}uiowa.edu

Respiratory viruses often express mechanisms to resist host antiviral systems, but the biochemical basis for evasion of interferon effects by respiratory syncytial virus (RSV) is poorly defined. In this study, we identified RSV effects on interferon (IFN)-dependent signal transduction and gene expression in human airway epithelial cells. Initial experiments demonstrated inhibition of antiviral gene expression induced by IFN- and IFN-ß, but not IFN-, in epithelial cells infected with RSV. Selective viral effects on type I IFN-dependent signaling were confirmed when we observed impaired type I, but not type II, IFN-induced activation of the transcription factor Stat1 in RSV-infected cells. RSV infection of airway epithelial cells resulted in decreased Stat2 expression and function with preservation of upstream signaling events, providing a molecular mechanism for viral inhibition of the type I IFN JAK-STAT pathway. Furthermore, nonspecific pharmacologic inhibition of proteasome function in RSV-infected cells restored Stat2 levels and IFN-dependent activation of Stat1. The results indicate that RSV acts on epithelial cells in the airway to directly modulate the type I IFN JAK-STAT pathway, and this effect is likely mediated though proteasome-dependent degradation of Stat2. Decreased antiviral gene expression in RSV-infected airway epithelial cells may allow RSV replication and establishment of a productive viral infection through subversion of IFN-dependent immunity.

Abbreviations: analysis of variance, ANOVA • human tracheobronchial epithelial, hTBE • IFN- receptor, IFNAR • IFN- receptor, IFNGR • interferon regulatory factor, IRF • interferon-stimulated gene factor 3, ISGF3 • intercellular adhesion molecule-1, ICAM-1 • Janus family kinase, JAK • Laboratory of Human Carcinogenesis, LHC • lactate dehydrogenase, LDH • major histocompatibility complex, MHC • multiplicity of infection, m.o.i. • not detected, ND • plaque-forming units, PFU • protein kinase R, PKR • respiratory syncytial virus, RSV • signal transducer and activator of transcription, STAT

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