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.