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的致病性是通过同时抑制宿主免疫反应和增强病毒蛋白质和RNA的产生来实现的。然而，人们对埃博拉病毒与宿主细胞之间促进病毒感染和繁殖的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剂。这些因素结合在一起，强调了对埃博拉病毒组分进行详细结构和功能表征的必要性。埃博拉病毒VP 35蛋白是病毒生命周期中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。该研究利用重组表达的非感染性VP 35蛋白，将检测VP 35的结构，并使用生物化学方法表征其抗病毒活性。这些研究将显著提高我们对VP 35如何增强病毒发病机制的理解，并促进新的诊断和治疗策略的设计，以破坏关键的宿主-病原体相互作用。公共卫生相关性：越来越多的人担心埃博拉病毒在人群中爆发的罕见但不断增加，加上以生物恐怖主义形式滥用的可能性增加，强调了更好地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的重要性。埃博拉病毒VP 35负责免疫抑制，它可以增强病毒复制。本提案中描述的工作将表征埃博拉病毒VP 35蛋白的先天免疫拮抗作用的结构和机制基础，这将为治疗干预和细胞生物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.