Ning Yun-Jia, Feng Kuan, Min Yuan-Qin, Cao Wu-Chun, Wang Manli, Deng Fei, Hu Zhihong, Wang Hualin
State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
Department of Immunology, School of Medicine, Wuhan University, Wuhan, China.
J Virol. 2015 Apr;89(8):4227-36. doi: 10.1128/JVI.00154-15. Epub 2015 Jan 28.
The type I interferon (IFN) system, including IFN induction and signaling, is the critical component of the host defense line against viral infection, which, in turn, is also a vulnerable target for viral immune evasion. Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging bunyavirus. Previous data have shown that SFTSV can interfere with the early induction of type I IFNs through targeting host kinases TBK1/IKKε. In this study, we demonstrated that SFTSV also can suppress type I IFN-triggered signaling and interferon-stimulated gene (ISG) expression. Interestingly, we observed the significant inhibition of IFN signaling in cells transfected with the plasmids encoding the nonstructural protein (NSs) but not the nucleocapsid protein (NP), indicating the role of NSs as an antagonist of IFN signaling. Furthermore, coimmunoprecipitation (Co-IP) and pulldown assays indicated that NSs interacts with the cellular signal transducer and activator of transcription 2 (STAT2), and the DNA-binding domain of STAT2 may contribute to the NSs-STAT2 interaction. Combined with confocal microscopy analyses, we demonstrated that NSs sequesters STAT2 and STAT1 into viral inclusion bodies (IBs) and impairs IFN-induced STAT2 phosphorylation and nuclear translocation of both STATs, resulting in the inhibition of IFN signaling and ISG expression. SFTSV NSs-mediated hijacking of STATs in IBs represents a novel mechanism of viral suppression of IFN signaling, highlighting the role of viral IBs as the virus-built "jail" sequestering some crucial host factors and interfering with the corresponding cellular processes.
SFTSV is an emerging bunyavirus which can cause a severe hemorrhagic fever-like disease with high case fatality rates in humans, posing a serious health threat. However, there are no specific antivirals available, and the pathogenesis and virus-host interactions are largely unclear. Here, we demonstrated that SFTSV can inhibit type I IFN antiviral signaling by the NSs-mediated hijacking of STAT2 and STAT1 into viral IBs, highlighting the interesting role of viral IBs in virus-host interactions as the virus-built jail. Sequestering signaling molecules into IBs represents a novel and, perhaps, also a general mechanism of viral suppression of IFN signaling, the understanding of which may benefit the study of viral pathogenesis and the development of antiviral therapies.
I型干扰素（IFN）系统，包括IFN的诱导和信号传导，是宿主抵御病毒感染防线的关键组成部分，而这反过来也是病毒免疫逃逸的脆弱靶点。严重发热伴血小板减少综合征病毒（SFTSV）是一种新出现的布尼亚病毒。先前的数据表明，SFTSV可通过靶向宿主激酶TBK1/IKKε来干扰I型IFN的早期诱导。在本研究中，我们证明SFTSV还可抑制I型IFN触发的信号传导和干扰素刺激基因（ISG）的表达。有趣的是，我们观察到在转染了编码非结构蛋白（NSs）而非核衣壳蛋白（NP）的质粒的细胞中，IFN信号传导受到显著抑制，这表明NSs作为IFN信号传导拮抗剂的作用。此外，免疫共沉淀（Co-IP）和下拉试验表明，NSs与细胞信号转导和转录激活因子2（STAT2）相互作用，并且STAT2的DNA结合结构域可能有助于NSs与STAT2的相互作用。结合共聚焦显微镜分析，我们证明NSs将STAT2和STAT1隔离到病毒包涵体（IBs）中，并损害IFN诱导的STAT2磷酸化以及两种STAT蛋白的核转位，从而导致IFN信号传导和ISG表达受到抑制。SFTSV的NSs介导的在IBs中劫持STAT蛋白代表了病毒抑制IFN信号传导的一种新机制，突出了病毒IBs作为病毒构建的“监狱”隔离一些关键宿主因子并干扰相应细胞过程的作用。
SFTSV是一种新出现的布尼亚病毒，可在人类中引起具有高病死率的严重出血热样疾病，对健康构成严重威胁。然而，目前尚无特效抗病毒药物，其发病机制和病毒-宿主相互作用在很大程度上尚不清楚。在此，我们证明SFTSV可通过NSs介导的将STAT2和STAT1劫持到病毒IBs中来抑制I型IFN抗病毒信号传导，突出了病毒IBs在病毒-宿主相互作用中作为病毒构建的“监狱”的有趣作用。将信号分子隔离到IBs中代表了病毒抑制IFN信号传导的一种新的且可能也是普遍的机制，对其的理解可能有益于病毒发病机制的研究和抗病毒疗法的开发。
