The Impact of Innate Neuronal Immunity on Neurotropic Arbovirus Pathogenesis

描述(申请人提供)：天生的细胞抗病毒反应是抵御病毒感染的基本第一道防线，也在启动适应性免疫从而最终控制或清除病毒方面发挥关键作用。然而，先天性免疫反应的不适当激活也可能导致病毒的发病。因此，抑制或加强先天抗病毒反应步骤的细胞内通路是宿主-病原体相互作用的关键组成部分，最终决定病毒感染的结果。此外，对这些途径背后的细胞和分子机制的详细了解对于设计新型抗病毒或免疫调节药物非常重要。尽管我们对细胞固有抗病毒反应的了解在过去十年中取得了巨大的进步，但仍然存在重大差距。例如，先天抗病毒免疫反应由复杂的相互作用网络组成，表现出细胞类型和病原体特异性的差异，但这些差异在病毒发病机制中的功能意义和影响，特别是在中枢神经系统中，尚未得到很好的研究。我们假设，依赖于内在成熟的先天抗病毒反应是嗜神经病毒感染发病的关键决定因素。我们建议使用西方马脑炎病毒(Weev)在人类神经细胞中探索这些反应，Weev是一种蚊媒传播的正链RNA病毒，属于Togaviridae家族(属：甲型病毒)。Weev和密切相关的东部和委内瑞拉马脑炎病毒是B类生物恐怖主义病原体，可引起中枢神经系统感染，与高临床发病率和死亡率有关，目前尚无有效的治疗方法。虫媒病毒疾病，例如由嗜神经性甲型病毒引起的疾病，在过去几十年里也被视为重大的公共卫生威胁。该项目的长期目标是阐明参与人类中枢神经系统神经元对虫媒病毒感染的固有抗病毒反应的细胞自主识别、激活和效应通路的分子机制。这项建议的重点是利用培养的人神经细胞采用定向和全局遗传和化学基因组方法来研究成熟神经元中负责Weev识别和启动先天抗病毒反应的激活途径。

Description (provided by applicant): Innate cellular antiviral responses are essential first lines of defense against viral infections, and also play crucial roles in the initiation of adaptive immunity and hence eventual virus control or clearance. However, the inappropriate activation of innate immune responses can also contribute to viral pathogenesis. Intracellular pathways that suppress or potentiate steps in innate antiviral responses therefore represent crucial components of the host-pathogen interactions that ultimately determine the outcome of viral infections. Furthermore, a detailed understanding of the cellular and molecular mechanisms underlying these pathways is important for the rationale design of novel antiviral or immunomodulatory drugs. Although our knowledge regarding innate cellular antiviral responses has progressed tremendously over the past decade, significant gaps still exist. For example, innate antiviral immune responses consist of a complex network of interactions that exhibit both cell type- and pathogen-specific differences, but the functional significance and impact of these differences on viral pathogenesis, particularly within the central nervous system, have not been well studied. We hypothesize that intrinsic maturation-dependent innate antiviral responses are key determinants in the pathogenesis of neurotropic virus infections. We propose to explore these responses in human neuronal cells using western equine encephalitis virus (WEEV), a mosquito-borne positive-strand RNA virus belonging to the Togaviridae family (genus: Alphavirus). WEEV and the closely related eastern and Venezuelan equine encephalitis viruses are category B bioterrorism agents, and cause central nervous system infections that are associated with high clinical morbidity and mortality for which there are no effective therapies. Arboviral diseases, such as those caused by neurotropic alphaviruses, have also seen both an emergence and resurgence as significant public health threats over the past several decades. The long-term objectives of this project are to elucidate the molecular mechanisms underlying the cell- autonomous recognition, activation, and effector pathways involved in the innate antiviral responses of human central nervous system neurons to arbovirus infections. The focus of this proposal is to employ targeted and global genetic and chemical genomic approaches with cultured human neuronal cells to examine the activation pathways responsible for WEEV recognition and initiation of innate antiviral responses in mature neurons.