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

描述（由申请人提供）：登革病毒（DENV）是全球最流行的节肢动物传播病毒，是一种新出现的全球健康威胁。没有预防DENV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，预防人类感染登革病毒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子。DENV宿主因子的鉴定和病毒利用这些因子促进其自身复制的分子机制的阐明是鉴定抗病毒分子的候选靶标的关键步骤。该提案的目标是鉴定细胞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人和蚊子细胞中DENV复制中的作用。使用生物化学和遗传学的方法相结合，我们建议阐明的机制，DENV挪用的细胞RBP多嘧啶道结合蛋白（PTB）的功能，以增加病毒复制。我们还将使用一种创新的方法来鉴定受感染的人类和蚊子细胞中细胞RBP和DENV RNA之间的新型相互作用。这项工作将显着推进DENV生物学领域，不仅告知我们对DENV复制的分子机制的理解，而且还揭示了抗病毒化合物的潜在候选靶点。

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.