Molecular Mechanisms Of The Interaction Between TBK1 And The Nonstructurale Protein NSs Of The Novel Bunyaviruses

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease. The major clinical symptoms are fever, thrombocytopenia and leukopenia. In critically ill SFTS patients, clinical conditions can deteriorate rapidly and end in multiorgan failure, and the fatality rate has been up to 15-30%. It was identified that a novel RNA virus that caused SFTS, and the virus is classified in the genus Phlebovirus, family Bunyaviridae, termed SFTS Virus (SFTSV). SFTSV transmits through ticks, and has recently also been identified in patients and ticks in Japan and Korea. In 2012, The US CDC reported that two strains of new bunyaviruses, named as Heartland Virus (HLV), had been isolated from two feverish and critically ill patients. Further analyses indicated that SFTSV and HLV are highly homologous. Thus, the new bunyavirus transmitted through ticks may be a type of novel and emerging pathogen which exists worldwide. Previous studies have showed that non-structural protein NSs could suppress the innate immunity. Through interacting with TBK1, a kinase that plays an important role in interferon signaling pathway, NSs could suppress interferon response, and facilitate the viral replication by translocating the TBKl,IKKe and IRF3 complex into viral inclusion bodies. This study aims to illuminate the molecular mechanism of the interaction between NSs and TBK1. The specific research objectives include:1. Verify the inhibitory effect of NSs on antiviral response in host cells and compare the interaction between NSs proteins from different viruses and TBK1; 2. Characterize Ihe functional region of the interaction between NSs and TBK1; and demonstrate the effect of the interaction between NSs and TBK1 on TBK1 kinase activity. Our results showed that both of the NSs proteins from SFTSV and HLV could suppress IFN-P response in infected cells, and there was no significant differences in the suppression function of NSs from different viruses. The interaction between SFTSV-NSs and TBK1 relied on the entire protein of TBK1, and SFTSV-NSs and HLV-NSs could suppress the phosphorylation of TBK1 and ERF3. However, the the interaction between SFTSV-NSs and TBK1 does not disrupt the interaction of TBK1 and ERF3. This study improved our understanding of the interaction between the novel Bunyaviruses and cells, ant the virus pathogenic mechanism.