Dual regulatory effects of SFTS virus NSs protein on interferon signaling

Abstract

Innate interferon (IFN) response that inhibits viral replication is the first-line host defense against viral infection. To circumvent this response, viruses have developed various countermeasures to antagonize IFN production and/or signaling. SFTS virus (SFTSV) is an emerging zoonotic pathogen initially identified in China and subsequently found in other parts of the world. SFTSV NSs protein is an IFN antagonist that has been shown to counteract type I IFN induction by targeting TBK1 and IKKε kinases and to impede IFN signaling by interacting with and sequestrating STAT2 in the cytoplasm. In this study, we demonstrated that SFTSV infection and its NSs protein suppresses both production and signaling of type I and type III IFNs by preventing STAT1 phosphorylation and activation whereas augments type II IFN signaling. In contrast, expression of NSs or infection with SFTSV had no influence on the activation of NF-κB signaling. NSs protein not only interacts with STAT1 and STAT2, but also inhibits IFN-β-induced phosphorylation at serine 727 of STAT1 without affecting serine 701 phosphorylation. Furthermore, STAT1 protein was inhibited at the transcriptional level. IRF1 and CXCl10 expression was further induced as a result of the increase in STAT1 phosphorylation in the presence of both IFN-γ and NSs. Taken together, our findings suggested that SFTSV NSs protein is a viral modulator of IFN signaling that has opposite effect on type I and type II IFN signaling. Our work provides new knowledge in SFTSV pathogenesis and has implications in the design and development of anti-SFTSV agents and vaccines. This work was supported by RGC-NSFC JRS (N-HKU 714/12), RGC CRF (HKU1/CRF/11G and C7011- 15R) and HMRF (HKM-15-M01).