Specific inhibition of interferon signal transduction pathways by adenoviral infection.
Adenoviral evolution has generated strategies to resist host cell antiviral systems, but molecular mechanisms for evasion of interferon (IFN) effects by adenoviruses during late-phase infection are poorly defined. In this study, we examined adenovirus type 5 (AdV) effects on IFN-gamma-dependent gene expression and Janus family kinase-signal transducer and activator of transcription signaling components in human tracheobronchial epithelial cells. We found that AdV infection specifically inhibited IFN-gamma-dependent gene expression in airway epithelial cells without evidence of epithelial cell injury or generation of a soluble extracellular inhibitor. Furthermore, infection with AdV for 18-24 h blocked phosphorylation/activation of the Stat1 transcription factor that regulates IFN-gamma-dependent genes. Although AdV also inhibited IFN-alpha-dependent phosphorylation of Stat1 and Stat2, interleukin-4-dependent phosphorylation of the related transcription factor Stat6 was not affected, indicating that the virus selectively affected specific signaling pathways. Our results indicate that AdV inhibition of the IFN-gamma signal transduction cascade occurs through loss of ligand-induced receptor complex assembly and consequent component phosphorylation and suggest that lack of complex assembly is due to decreased expression of the IFN-gammaR2 chain of the IFN-gamma receptor. IFN-gammaR2 is required at an early step in Janus family kinase-signal transducer and activator of transcription pathway activation and is expressed at low levels in airway epithelial cells, supporting the concept that adenoviral down-regulation of the level of this IFN-gamma receptor component allows for persistent modulation of IFN-gamma-dependent gene expression.
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Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
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D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism / Q000821:virology; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D015151:Immunoblotting; D007371:Interferon-gamma / Q000378:metabolism; D007372:Interferons / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism; D053613:Janus Kinase 1; D051379:Mice; D010766:Phosphorylation; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D050800:STAT6 Transcription Factor; D015398:Signal Transduction; D013997:Time Factors; D014132:Trachea / Q000378:metabolism / Q000821:virology; D015534:Trans-Activators / Q000378:metabolism
D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494080:Stat1 protein, mouse; C494085:Stat2 protein, mouse; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4; D007371:Interferon-gamma; D007372:Interferons; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1