当前，登革病毒的致病机理并不清楚，但逃逸宿主抗病毒天然免疫，特别是拮抗细胞I型干扰素的产生及其抗病毒免疫反应，被认为是登革病毒致病的重要环节。前期研究我们发现登革病毒编码蛋白NS4A抑制IRF3的转录激活，从而拮抗I型干扰素的产生以及下游抗病毒蛋白的表达。通过进一步的研究，我们发现NS4A蛋白与RLRs信号通路中的重要蛋白MAVS存在相互作用。以此为基础，本项目拟将系统性证明登革病毒NS4A蛋白拮抗I型干扰素生成的新功能；拟证明NS4A结合MAVS蛋白后，抑制RIG-I与MAVS复合物的形成，阻断信号的传递，最终拮抗I型干扰素的产生，介导登革病毒天然免疫逃逸的分子机制。本研究致力于阐明登革病毒如何通过靶向RLRs信号通路介导天然免疫逃逸，不仅对揭示登革病毒的致病机制具有重要的意义，而且为减毒活疫苗，以及抗病毒小分子抑制剂的研发奠定理论基础。

The pathogenic mechanism of DENV remains unclear. Nonetheless, it becomes clear that evasion of dengue virus from host antiviral innate immunity, particularly its antagonism against type I interferon production and the consequent antiviral immune responses, contributes to the pathogenesis of DENV. Recently, our preliminary results demonstrated that DENV-encoded protein NS4A inhibited the transcriptional activation of IRF3, and then antagonized the production of type I interferon and the expression of downstream antiviral proteins in host cells. Moreover, our studies showed that NS4A interacted with the key adaptor protein MAVS of the RLRs signaling pathways. Therefore, in the current project, on the one hand, we are aiming to systematically investigate the new biological functions of dengue virus NS4A in innate immunity evasion. On the other hand, we are aiming to demonstrate the molecular mechanism of dengue virus-mediated innate immunity evasion by which NS4A inhibits the formation of RIG-I-MAVS complexes, blocks the signal transduction, and ultimately antagonizes type I interferon production. Overall, the aim of this project is to clarify how dengue virus evades the innate immune through targeting the RLRs signaling pathway, and these findings will not only have important implications for revealing the pathogenesis of dengue virus, but also may facilitate future use of attenuated viruses as a potential live vaccine, and also small molecules directed against such antagonistic actions may have the potential to become anti-DENV therapeutics candidates.