甲流病毒通过Hippo信号通路效应蛋白YAP/TAZ抑制TLR3介导的先天免疫反应的机制研究

甲型流感病毒逃逸宿主先天免疫反应的能力增加了免疫系统抵抗感染以及抗病毒治疗的难度。因此，探索其免疫逃逸的机制至关重要。我们前期的研究结果显示：甲型流感病毒能够激活Hippo信号通路效应蛋白YAP/TAZ。同时,干扰Hippo信号通路影响了宿主细胞内甲流病毒的复制和增殖。此外，我们还发现了YAP/TAZ抑制了TLR3的转录表达。由此我们提出假设：甲流病毒通过激活YAP/TAZ抑制了TLR3介导的先天免疫信号通路。本项目将利用过表达/敲除关键基因、荧光酶素报告系统、染色质免疫沉淀和蛋白免疫共沉淀等实验技术进一步研究甲流病毒激活YAP/TAZ的机制以及YAP/TAZ调控TLR3表达的机理。同时,我们还将建立甲流病毒感染的小鼠模型，利用Yap敲除小鼠在体内验证Yap在甲流病毒感染中的作用。本研究将加深我们对流感病毒抵抗宿主先天免疫反应机制的了解，为流感病毒的防治提供新的思路和靶位点。

Evasion of host innate immune response by influenza A virus makes it difficult for human immune system and antiviral treatment to combat infection. It is, therefore, imperative to study its evasion strategies. Our previous study has showed that influenza A virus could activate YAP/TAZ, the effectors of the Hippo signaling pathway. Meantime, disruption of the Hippo signaling pathway, in turn, affects virus replication. Based on these findings, we hypothesized that influenza A virus activates YAP/TAZ to suppress TLR3-mediated innate immune signaling. Taking advantage of experimental techniques such as overexpression/loss of critical genes, luciferase reporter assay, chromatin immunoprecipitation and co-immunoprecipitation, we will continue to explore the molecular mechanism on regulation of activity of YAP/TAZ by influenza A virus, and also the regulation of TLR3 expression by YAP/TAZ. Besides, using Yap knock-out mice, we will establish a mouse model for influenza infection to verify the effect of Yap on influenza A virus infection. This research would deepen our understanding of the tactics exploited by influenza A virus to evade host innate immune system and propose potentially new strategies and targets for prevention and treatment of influenza.