寨卡病毒会引起神经系统相关重症疾病，但机理未明，有报道其非结构蛋白NS1、NS2A、NS4B均可负调节IFN-I产生；最新报道IFN-I通路阻断是西尼罗病毒突破血脑屏障的直接原因。因此推测寨卡病毒持续性拮抗IFN-I产生，为其神经系统致病的重要环节。我们前期新发现其NS4A及NS2B-3可能分别调控RLR通路的MAVS及STING信号而负调节IFN-I。由此，本项目首先拟系统证明NS4A和NS2B-3分别直接结合MAVS和STING，阻断其下游信号转导最终拮抗IFN-I产生。更为重要，证明IFN-I通路直接介导寨卡病毒感染下血脑屏障突破而侵犯神经系统；其机理为NS1、NS2A、NS2B-3、NS4A及NS4B协同拮抗IFN-I产生，使得病毒持续性增强感染脑微血管内皮细胞并增加血脑屏障通透性。本研究将阐明寨卡病毒非结构蛋白通过拮抗IFN-I产生而突破血脑屏障，揭示其神经系统致病的首要环节。

The pathogenic mechanism of zika virus (ZIKV) remains unclear. Nonetheless, it becomes clear that evasion of ZIKV from host antiviral innate immunity, particularly its antagonism against type I interferon production and the consequent antiviral immune responses, contributes to the neuropathogenesis of ZIKV. Recently, our preliminary results demonstrated that ZIKV-encoded protein NS4A and NS2B-3 antagonized the production of type I interferon and the expression of downstream antiviral proteins in host cells. Moreover, our studies showed that NS4A and NS2B-3, respectively interacted with the key adaptor protein MAVS and STING of the RLRs signaling pathways. Therefore, in the current project, firstly, we are aiming to systematically investigate the new biological functions of zika virus NS4A and NS2B-3 in innate immunity evasion. Secondly, we are aiming to demonstrate the molecular mechanism of zika virus-mediated innate immunity evasion by which NS4A and NS2B-3 inhibits the formation of RIG-I-MAVS-STING complexes, blocks the signal transduction, and ultimately antagonizes type I interferon production. Lastly, we are aiming to show that systemic spread of ZIKV from the site of infection to the brain requires IFN signaling deficiency triggered by several viral nonstructural protein (including NS1, NS2A, NS2B-3, NS4A and NS4B). Within this context, ZIKV infection of brain microvascular endothelial cell and astrocytes results in breakdown of the blood–brain barrier. Overall, the aim of this project is to clarify how zika virus evades the innate immune through targeting the RLRs signaling pathway, and these findings will not only have important implications for revealing the neuropathogenesis of ZIKV.