Structural studies of Ebola VP35 mediated immune evasion mechanisms

描述（由申请人提供）：埃博拉病毒是a类优先病原体，是病毒性出血热的病原体。埃博拉病毒表现出的增强致病性是通过同时抑制宿主免疫反应和增强病毒蛋白和RNA的产生来实现的。然而，人们对埃博拉病毒与促进病毒感染和传播的宿主细胞之间相互作用的确切性质知之甚少。因此，目前没有针对埃博拉病毒的疫苗或抗病毒药物。这些因素结合在一起，强调需要对埃博拉病毒成分进行详细的结构和功能表征。埃博拉病毒VP35蛋白是病毒生命周期几个阶段所需的重要毒力因子，包括病毒组装、基因组复制、包装、病毒转录和对宿主先天免疫系统的抗病毒活性。该研究计划的总体目标是探索导致免疫逃避的宿主-病毒相互作用。该研究将利用重组表达的非感染性VP35蛋白，检测VP35的结构，并利用生化方法表征其抗病毒活性。这些研究将大大提高我们对VP35如何增强病毒发病机制的理解，并促进设计新的诊断和治疗策略，以破坏关键的宿主-病原体相互作用。公共卫生相关性：人们日益关注埃博拉病毒在人群中罕见但不断增加的爆发，再加上以生物恐怖主义形式滥用的可能性越来越大，这突出表明必须进一步了解使埃博拉病毒对全球人类健康构成重大威胁的病毒成分。埃博拉病毒VP35负责免疫抑制，它可以增强病毒复制。本文所描述的工作将表征埃博拉病毒VP35蛋白先天免疫拮抗的结构和机制基础，为治疗干预和细胞生物学试剂的设计提供潜在的靶点。

DESCRIPTION (provided by applicant): Ebola virus is a category A priority pathogen and a causative agent of viral hemorrhagic fever. Enhanced pathogenicity displayed by the Ebola virus is achieved through simultaneous inhibition of host immune responses and enhanced production of viral proteins and RNA. However, the exact nature of the interactions between the Ebola virus and host cells that promote viral infection and propagation are poorly understood. Consequently, no vaccines or antiviral agents against Ebola are currently available. These factors combined, underscore the need for detailed structural and functional characterization of the Ebola viral components. Ebola VP35 protein is an important virulence factor required in several viral lifecycle stages, including viral assembly, genome replication, packaging, viral transcription, and antiviral activity toward the host innate immune system. Overall goal of the research program is to explore host-viral interactions that lead to immune evasion. The proposed study, using recombinantly expressed non-infectious VP35 protein, will examine the structure of VP35 and characterize its antiviral activity using biochemical methods. These studies will significantly improve our understanding of how VP35 functions to enhance viral pathogenesis and facilitate the design of novel diagnostic and therapeutic strategies to disrupt critical host-pathogen interactions. PUBLIC HEALTH RELEVANCE: Growing concerns of rare but increasing Ebola outbreaks among human populations, coupled with a rising potential of misuse in the form of bioterrorism, underscore the importance of developing a greater understanding of viral components that make Ebola virus a significant threat to global human health. Ebola VP35 is responsible for immune suppression and it can enhance viral replication. Work described in this proposal will characterize the structure and mechanistic basis for innate immune antagonism by Ebola viral VP35 protein, which will provide potential targets to therapeutic interventions and design of cell biological reagents.