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

描述（由申请人提供）：登革热病毒（DENV）是世界上最流行的节肢动物传播病毒，也是一种新兴的全球健康威胁。目前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DENV感染的唯一方法是防止接触传播该病毒的蚊子媒介。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自身复制的分子机制的阐明是确定抗病毒分子候选靶点的关键步骤。本研究的目的是确定细胞RNA结合蛋白（RBP）与DENV RNA之间的相互作用，并表征这些相互作用在调节人类和蚊子细胞中DENV复制中的作用。采用生物化学和遗传学相结合的方法，我们建议阐明DENV利用细胞RBP多嘧啶路结合蛋白（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鉴定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。这项工作不仅使我们了解了DENV复制的分子机制，而且揭示了抗病毒化合物的潜在候选靶点，将显著推进DENV生物学领域的发展。

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.