The Nonstructural Protein NSs of Severe Fever with Thrombocytopenia Syndrome Virus Causes a Cytokine Storm through the Hyperactivation of NF-B.

Severe fever with thrombocytopenia syndrome (SFTS) virus (SFTSV) is an emerging highly pathogenic phlebovirus. The syndrome is characterized by the substantial production of inflammatory cytokines and chemokines, described as a cytokine storm, which correlates with multiorgan failure and high mortality. SFSTV nonstructural (NSs) protein was suggested to mediate the pathogenesis by inhibiting antiviral interferon signaling in the host. However, whether SFTSV NSs protein mediates the induction of a fatal cytokine storm remains unaddressed. We demonstrated that SFTSV NSs promotes the hyperinduction of cytokine/chemokine genes , reminiscent of a cytokine storm. Using gene deletion and pharmacological intervention, we found that the induced cytokine storm is driven by the transcription factor NF-B. Our investigation revealed that TANK-binding kinase 1 (TBK1) suppresses NF-κB signaling and cytokine/chemokine induction in a kinase activity-dependent manner and that NSs sequesters TBK1 to prevent it from suppressing NF-κB, thereby promoting the activation of NF-κB and its target cytokine/chemokine genes. Of note, NF-κB inhibition suppressed the induction of proinflammatory cytokines in SFTSV-infected type I interferon (IFN-I) receptor 1-deficient () mice. These findings establish the essential role of NSs in SFTS pathogenesis and suggest NF-κB as a possible therapeutic target.