寨卡病毒属黄病毒科，主要通过蚊子传播。许多寨卡病毒感染病例是无症状的，感染最常见的症状是皮疹、发烧和关节疼痛。然而，一些流行病学数据强烈表明，孕妇在怀孕期间感染寨卡病毒使新生儿患有小头症的风险极大增加。我们的前期结果显示，寨卡病毒的两个非结构蛋白NS4A和NS4B通过抑制Akt-mTOR通路来诱导自噬反应，并抑制神经干细胞的增殖与分化，但是其作用的具体分子机制不明。本项目拟在前期研究的基础上，主要研究寨卡病毒如何诱导宿主的自噬以及自噬在病毒生命周期中的作用。一方面申请人将通过生物化学和分子生物学手段深入探讨NS4A和NS4B的作用机理、找到其抑制Akt-mTOR通路的作用靶点。另一方面，通过自噬基因缺陷小鼠结合已有的IFNAR1敲除小鼠感染模型来检测细胞的自噬反应对寨卡病毒感染复制和致病的影响。该项目的顺利实施可以加深人们对寨卡病毒感染致病机理的理解，为抗病毒治疗提供新思路。

Zika virus (ZIKV) belongs to a positive single-stranded RNA Flavivirus family, and is spread by the infected Aedes mosquito. Many cases of ZIKV infection are asymptomatic, the most common symptoms of infection being rash, fever, and joint pain. However, a number of epidemiology data strongly indicate that newborns of mothers who had ZIKV infection during pregnancy are at an increased risk for microcephaly. Our preliminary data suggested that ZIKV NS4A and NS4B inhibit Akt-mTOR signaling to induce autophagy but downregulate neurogenesis of neural stem cells. Thus, the primary goal of this study is to investigate how ZIKV induces host’s autophagy for its viral lifecycle. On one hand, we will use biochemistry and molecular approach to dissect the molecular mechanism by which NS4A and NS4B block Akt-mTOR pathway. On the other hand, we will use Atg5 knockout mice to study the role of autophagy in ZIKV replication and pathogenesis in vivo. The outcome of this study will improve the understanding of ZIKV pathogenesis and provide the molecular basis for anti-ZIKV drug development.