The Non-structural Protein NSs of SFTSV Causes Cytokine Storm Through the Hyper-activation of NF-κB.
Jumana KhalilShintaro YamadaYuta TsukamotoHiroto AbeMasayuki ShimojimaHiroki KatoTakashi FujitaPublished in: Molecular and cellular biology (2020)
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-κB. Our investigation revealed that TANK-binding kinase 1 (TBK1) suppresses NF-κB signaling and cytokine/chemokine induction in its 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 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-κB as a possible therapeutic target.
Keyphrases
- signaling pathway
- lps induced
- pi k akt
- nuclear factor
- oxidative stress
- transcription factor
- randomized controlled trial
- dendritic cells
- genome wide
- inflammatory response
- cardiovascular disease
- type diabetes
- immune response
- protein protein
- amino acid
- coronary artery disease
- toll like receptor
- cardiovascular events
- endothelial cells
- skeletal muscle
- single cell
- dna methylation
- early onset
- cell proliferation
- dna binding