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Disruption of Type I Interferon Signaling by the Nonstructural Protein of Severe Fever with Thrombocytopenia Syndrome Virus via the Hijacking of STAT2 and STAT1 into Inclusion Bodies

ABSTRACT 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. IMPORTANCE 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.