Ramaswamy Murali, Shi Lei, Monick Martha M, Hunninghake Gary W, Look Dwight C
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, USA.
Am J Respir Cell Mol Biol. 2004 Jun;30(6):893-900. doi: 10.1165/rcmb.2003-0410OC. Epub 2004 Jan 12.
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-alpha and IFN-beta, but not IFN-gamma, 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.
呼吸道病毒常常表达抵抗宿主抗病毒系统的机制，但呼吸道合胞病毒（RSV）逃避干扰素作用的生化基础仍不清楚。在本研究中，我们确定了RSV对人气道上皮细胞中干扰素（IFN）依赖性信号转导和基因表达的影响。初步实验表明，在感染RSV的上皮细胞中，IFN-α和IFN-β诱导的抗病毒基因表达受到抑制，但IFN-γ诱导的抗病毒基因表达未受抑制。当我们观察到在RSV感染的细胞中I型（而非II型）IFN诱导的转录因子Stat1激活受损时，证实了RSV对I型IFN依赖性信号传导具有选择性病毒效应。气道上皮细胞感染RSV导致Stat2表达和功能下降，而上游信号事件得以保留，这为病毒抑制I型IFN JAK-STAT途径提供了一种分子机制。此外，对RSV感染细胞中蛋白酶体功能的非特异性药理抑制恢复了Stat2水平以及Stat1的IFN依赖性激活。结果表明，RSV作用于气道中的上皮细胞，直接调节I型IFN JAK-STAT途径，并且这种效应可能是通过蛋白酶体依赖性降解Stat2介导的。RSV感染的气道上皮细胞中抗病毒基因表达的降低可能使RSV通过破坏IFN依赖性免疫进行复制并建立有效的病毒感染。
