人类呼吸道病毒是人类最普遍的疾病原因,高传染性RSV是婴儿细支气管炎和病毒性肺炎的主要原因。对I型IFN的反应是针对病毒感染的主要防御。然而,RSV蛋白已被证明拮抗I型IFN介导的抗病毒先天免疫,特异性抑制细胞内IFN信号传导。呼吸道上皮细胞是RSV感染的主要目标。在这项研究中,我们发现RSV-NS1干扰了上皮细胞的IFN-αJAK/STAT信号通路。RSV-NS1表达显着增强IFN-α介导的STAT1磷酸化,但不增强pSTAT2;RSV-NS1对STAT1和STAT2总蛋白水平均无影响。然而,RSV-NS1的表达显著降低ISRE和GAS启动子活性和抗病毒IRG表达。进一步的机制研究表明RSV-NS1结合STAT1,蛋白质模型表明STAT1和RSV-NS1之间可能的相互作用位点。STAT1的核易位在RSV-NS1存在下减少。此外,STAT1与核运输衔接蛋白的相互作用,KPNA1,也减少了,提示RSV阻断STAT1核易位的机制。的确,减少STAT1进入细胞核可能解释RSV抑制IFNJAK/STAT启动子激活和抗病毒基因诱导。总之,这些结果描述了RSV控制抗病毒IFN-αJAK/STAT应答的新机制,这增强了我们对RSV呼吸道疾病进展的理解。
Human respiratory viruses are the most prevalent cause of disease in humans, with the highly infectious RSV being the leading cause of infant bronchiolitis and viral pneumonia. Responses to type I IFNs are the primary defense against viral infection. However, RSV proteins have been shown to antagonize type I IFN-mediated antiviral innate immunity, specifically dampening intracellular IFN signaling. Respiratory epithelial cells are the main target for RSV infection. In this study, we found RSV-NS1 interfered with the IFN-α JAK/STAT signaling pathway of epithelial cells. RSV-NS1 expression significantly enhanced IFN-α-mediated phosphorylation of STAT1, but not pSTAT2; and neither STAT1 nor STAT2 total protein levels were affected by RSV-NS1. However, expression of RSV-NS1 significantly reduced ISRE and GAS promoter activity and anti-viral IRG expression. Further mechanistic studies demonstrated RSV-NS1 bound STAT1, with protein modeling indicating a possible interaction site between STAT1 and RSV-NS1. Nuclear translocation of STAT1 was reduced in the presence of RSV-NS1. Additionally, STAT1\'s interaction with the nuclear transport adapter protein, KPNA1, was also reduced, suggesting a mechanism by which RSV blocks STAT1 nuclear translocation. Indeed, reducing STAT1\'s access to the nucleus may explain RSV\'s suppression of IFN JAK/STAT promoter activation and antiviral gene induction. Taken together these results describe a novel mechanism by which RSV controls antiviral IFN-α JAK/STAT responses, which enhances our understanding of RSV\'s respiratory disease progression.