SFTSV NSs sequesters the complex of SFTSV NP-SAFA to suppress SAFA mediated immune response.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging pathogenic bunyavirus with a high fatality rate of up to 30%. SFTSV nonstructural protein (NSs) forms viroplasm-like structures in the cytoplasm of infected cells, sequestering antiviral proteins and inhibiting interferon signaling. Nuclear scaffold attachment factor A (SAFA), a novel cytoplasmic RNA sensor, recognizes SFTSV infection and facilitates antiviral immune response. Intriguingly, we discovered that SFTSV NSs triggers nucleocytoplasmic translocation of SAFA. Nevertheless, whether the interaction between SAFA and NSs mediates the suppression of host innate immunity remains unresolved. Herein, we demonstrate that after SFTSV infection, SAFA retains in cytoplasm by interacting with NP, meanwhile, NSs captures NP- SAFA complex into inclusion bodies (IBs) through direct interaction with SPRY, AAA+ and RGG domains of SAFA, without affecting its expression levels. The activated SAFA initiates the STING-TBK1 axis, which is also sequestered by NSs into IBs, preventing p-IRF3 nuclear translocation and IFNβ production. In conclusion, our study reveals a novel immune evasion strategy of SFTSV involving sequestration of SAFA to suppress IFNβ secretion. These findings establish NSs as a virulence factor and identify SAFA as a promising broad-spectrum vaccine target against SFTSV and related pathogens.

发热伴血小板减少综合征病毒（Severe fever with thrombocytopenia syndrome virus, SFTSV）是一种新兴的致病性布尼亚病毒，致死率最高可达30%。SFTSV非结构蛋白（nonstructural protein, NSs）可在感染细胞的胞质内形成类病毒质结构，通过隔离抗病毒蛋白进而抑制干扰素信号通路。核骨架附着因子A（nuclear scaffold attachment factor A, SAFA）作为一种新型胞质RNA感受器，可识别SFTSV感染并激活抗病毒免疫应答。有趣的是，本研究发现SFTSV NSs可诱导SAFA发生核质穿梭。然而，SAFA与NSs的相互作用是否介导宿主固有免疫的抑制，这一问题仍未阐明。本研究证实：SFTSV感染后，SAFA可通过与核蛋白（nucleoprotein, NP）相互作用滞留于胞质；与此同时，NSs可通过与SAFA的SPRY、AAA+及RGG结构域直接结合，将NP-SAFA复合物招募至包涵体（inclusion bodies, IBs）中，且不影响SAFA的表达水平。激活的SAFA可启动STING-TBK1信号轴，而该信号轴同样可被NSs招募至IBs中，进而阻断磷酸化IRF3（phosphorylated IRF3, p-IRF3）的核转位以及β干扰素（interferon β, IFNβ）的产生。综上，本研究揭示了SFTSV的一种全新免疫逃逸策略：通过隔离SAFA以抑制IFNβ的分泌。本研究结果证实NSs是SFTSV的毒力因子，并确定SAFA是针对SFTSV及其相关病原体的潜在广谱疫苗靶点。