蚊媒人类病毒感染蚊子的受体机制研究

In the initialization of viral infection, the viral entry into host cells is mediated by the interaction between the viral surface proteins and cellular receptors. The receptors, which are key factors of viral invasion, are deemed to be one of dominant targets for vaccine and drug design. Mosquitoes transmit many human pathogenic viruses that show medical importance throughout the world. However, the mechanisms of the entry of mosquito-borne viruses are poorly understood in its arthropod vectors. Our previous studies have identified a dual-receptor system to facilitate West Nile virus (Cell, 2010) and Dengue infection (PLoS Pathogens, 2014) in Aedes aegypti. Therein, multiple C-type lectins serve as soluble receptors to recognize the virions and enhance the viral infection by bridging the virions to specific cellular receptors. In this study, we plan to investigate the entry mechanism of several important mosquito-borne viruses in A. aegypti, identify their viral receptors, and subsequently develop a novel vaccine strategy to interrupt the viral transmission. This study will substantially extend our understanding of mosquito-borne viral infection in vectors and provides a research avenue by which the development of therapeutics for preventing the dissemination of mosquito-borne viral diseases can be pursued in the future.

受体蛋白是病毒感染宿主细胞的关键因子，也是抗病毒疫苗及药物干预的主要靶点。蚊媒传播的人类病毒 (蚊媒病毒) 感染节肢动物媒介的受体机制非常复杂，其生物学机制远没有得到充分研究。申请人在之前的工作中鉴定出西尼罗病毒 (Cell, 2010) 及登革热病毒 (PLoS Pathogens, 2014) 利用一种二级受体机制感染埃及伊蚊细胞，其中多种C型凝集素作为分泌型受体在病毒感染中起到关键作用。在本项目的研究中，我们将选取多种重要蚊媒人类病毒、利用埃及伊蚊及转基因小鼠作为研究模型，系统性的解析蚊媒病毒感染节肢动物媒介的受体机制和自然规律，并利用病毒受体作为干预靶点研发抗病毒传播阻断疫苗策略，为抗蚊媒病毒新型疫苗的研制奠定理论及实践基础。

本项目的研究方向为系统性的解析蚊媒病毒感染其节肢动物媒介的受体机制和自然规律。深入研究“病毒-媒介-宿主”的互作关系，利用鉴定出的关键干预靶点研发登革病毒传播阻断疫苗，阐明蚊媒病毒在自然界中感染传播的分子机制，为蚊媒病毒防控奠定理论和实践基础。在本项目的资助下，我们已在相关领域取得了一系列的具有创新性和国际影响的研究成果。共发表通讯作者及共同通讯作者论文11篇，研究成果包括首次阐明寨卡病毒在自然界突然暴发的分子机制 (Nature, 2017)，深入研究媒介昆虫肠道微生物维持稳态及与病毒感染的互作关系 (Cell Host & Microbe 2019；Nature Microbiology, 2016; Nature Microbiology, 2017)，阐明媒介蚊虫对病毒易感的分子机制 (Nature Microbiology, 2019；Nature Communication, 2017)。授权国家发明专利5项，申请PCT国际专利2项。多次参与组织大型国际会议。培养博士研究生6名、博士后3名。总体来说，项目执行人已经顺利完成了项目设定的目标。

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