The role of host RNA-binding proteins in regulating dengue virus replication

描述(申请人提供)：登革病毒(DENV)是全球最流行的节肢动物传播病毒，是一种新的全球健康威胁。目前还没有预防登革热病毒感染的疫苗，也没有治疗登革热相关疾病的抗病毒药物。目前，预防人类感染DENV的唯一方法是防止接触传播病毒的蚊子媒介。DENV的复制依赖于宿主细胞提供的因素。确定DENV宿主因子并阐明病毒利用这些因子促进自身复制的分子机制是确定抗病毒分子候选靶点的关键步骤。这项建议的目的是确定细胞RNA结合蛋白(RBP)和DENV RNA之间的相互作用，并表征这些相互作用在调节DENV在人和蚊子细胞中复制的作用。利用生化和遗传学相结合的方法，我们建议阐明DENV利用细胞内RBP多嘧啶结合蛋白(PTB)的功能来增强病毒复制的机制。我们还将使用一种创新的方法来识别受感染的人和蚊子细胞中细胞RBP和DENV RNA之间的新相互作用。这项工作将极大地推动DENV生物学领域的发展，不仅使我们了解DENV复制的分子机制，而且还揭示了潜在的抗病毒化合物候选靶点。

DESCRIPTION (provided by applicant): Dengue virus (DENV) is the most prevalent arthropod-borne virus worldwide and an emerging global health threat. There is no vaccine for preventing DENV infection and no anti-viral drugs for treating dengue-related disease. Currently, the only method of preventing DENV infection in humans is preventing exposure to mosquito vectors that transmit the virus. Replication of DENV is dependent on factors provided by the host cell. The identification of DENV host factors and elucidation of the molecular mechanisms by which the virus exploits these factors to promote its own replication are critical steps in identifying candidate targets for anti- viral molecules. The goal of this proposal is to identify interactions between cellular RNA-binding proteins (RBP) and DENV RNA and to characterize the role of these interactions in regulating DENV replication in both human and mosquito cells. Using a combination of biochemical and genetic approaches, we propose to elucidate the mechanism by which DENV appropriates the function of the cellular RBP polypyrimidine-tract binding protein (PTB) to augment virus replication. We will also use an innovative approach to identify novel interactions between cellular RBP and DENV RNA in infected human and mosquito cells. This work will significantly advance the field of DENV biology by not only informing our understanding of the molecular mechanisms of DENV replication but also by revealing potential candidate targets for anti-viral compounds.