Structural studies of Ebola VP35 mediated immune evasion mechanisms

埃博拉VP35介导的免疫逃避机制的结构研究

基本信息

批准号：
7874657
负责人：
Gaya K. Amarasinghe
金额：
$ 52.37万
依托单位：
IOWA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7874657
关键词：
Antiviral Agents Attention Attenuated Be++ element Beryllium Binding Biochemical Biological Bioterrorism C-terminal Categories Cells Collaborations Complement Complex Coupled Data Disease Outbreaks Double-Stranded RNA Double-Stranded RNA Binding Domain Ebola virus Elements Genes Genetic Transcription Genome Goals Growth Health Human Immune Immune response Immune system Immunosuppression In Vitro Indium Infection Interferon Activation Interferons Knowledge Laboratories Lead Length Mediating Methods Modeling Molecular Mutation N-terminal Natural Immunity Nature Pathogenesis Pathogenicity Polymerase Population Production Property Proteins RNA RNA Binding Reagent Recombinants Reporting Research Resources Role Signal Transduction Staging Stress Structure Surface Testing Therapeutic Therapeutic Intervention Translations Vaccines Viral Viral Hemorrhagic Fevers Viral Packaging Viral Pathogenesis Viral Proteins Virulence Virulence Factors Virus Diseases Work base cofactor combat design eIF-2 Kinase human IRF3 protein improved in vivo innovation insight interferon regulatory factor-3 loss of function medical schools multidisciplinary mutant novel diagnostics novel strategies pathogen programs public health relevance research study response therapy design vaccine development viral RNA

项目摘要

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.

描述（由申请人提供）：埃博拉病毒是 A 类优先病原体，也是病毒性出血热的病原体。埃博拉病毒的致病性增强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宿主细胞之间促进病毒感染和传播的相互作用的确切性质知之甚少。因此，目前还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多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、病毒转录和针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。拟议的研究使用重组表达的非感染性 VP35 蛋白，将检查 VP35 的结构，并使用生化方法表征其抗病毒活性。这些研究将显着提高我们对 VP35 如何发挥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：人们对埃博拉病毒在人群中爆发的罕见但日益增加的担忧日益增加，加上以生物恐怖主义形式滥用的可能性不断增加，强调了进一步了解使埃博拉病毒对全球人类构成重大威胁的病毒成分的重要性。健康。埃博拉病毒 VP35 负责免疫抑制，并且可以增强病毒复制。该提案中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，这将为治疗干预和细胞生物试剂的设计提供潜在靶标。