| First Author | Khalil J | Year | 2020 |
| Journal | Mol Cell Biol | PubMed ID | 33288641 |
| Mgi Jnum | J:307042 | Mgi Id | MGI:6710218 |
| Doi | 10.1128/MCB.00542-20 | Citation | Khalil J, et al. (2020) The Non-structural Protein NSs of SFTSV Causes Cytokine Storm Through the Hyper-activation of NF-kappaB. Mol Cell Biol |
| abstractText | 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 cytokine storm, which correlates with multi-organ 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 fatal cytokine storm remains unaddressed. We demonstrated that SFTSV NSs promotes the hyper-induction of cytokine/chemokine genes in vitro, reminiscent of cytokine storm. Using gene deletion and pharmacological intervention, we found that the induced cytokine storm is driven by the transcription factor NF-kappaB. Our investigation revealed that TANK-binding kinase 1 (TBK1) suppresses NF-kappaB signaling and cytokine/chemokine induction in its kinase activity-dependent manner, and that NSs sequesters TBK1 to prevent it from suppressing NF-kappaB, thereby promoting the activation of NF-kappaB and its target cytokine/chemokine genes. Of note, NF-kappaB inhibition suppressed the induction of pro-inflammatory cytokines in SFTSV-infected type I interferon (IFN-I) receptor 1-deficient (Ifnar1-/-) mice. These findings establish the essential role of NSs in SFTS pathogenesis and suggest NF-kappaB as a possible therapeutic target. |
