Interactions of Ebola virus glycoproteins with host cells

埃博拉病毒糖蛋白与宿主细胞的相互作用

• 批准号: 7791766
• 负责人: Paul Bates
• 金额: $ 39.42万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7791766
• 关键词: Affect; Antiviral Agents; Arenavirus; Biochemical; Biology; Bioterrorism; Blood Vessels; Categories; Cathepsins; Cell Adhesion; Cell Communication; Cell Surface Proteins; Cell surface; Cells; Data; Democratic Republic of the Congo; Disease; Down-Regulation; Ebola virus; Employee Strikes; Endosomes; Endothelial Cells; Extravasation; Filovirus; Fright; Genetic; Glycoproteins; Goals; HIV; HIV-1; Human; Immune; Infection; Integration Host Factors; Interferons; Knowledge; MHC Class I Genes; Manuscripts; Mediating; Membrane Fusion; Membrane Glycoproteins; Membrane Proteins; Modeling; Mucins; Pathogenesis; Pathology; Pathway interactions; Peptide Hydrolases; Play; Proteins; Proteolysis; Proteomics; Publishing; Reporting; Research; Research Proposals; Retroviridae; Roentgen Rays; Role; Series; Structure; Surface; Testing; Therapeutic; Therapeutic Intervention; United States National Institutes of Health; Vaccines; Viral; Virion; Virus; Virus Diseases; Virus Replication; Work; blocking factor; design; effective therapy; mortality; new therapeutic target; novel; particle; pathogen; programs; protein expression; public health relevance; receptor; research study; ubiquitin-protein ligase; vpu Protein

DESCRIPTION (provided by applicant): Ebola viruses are among the most lethal human pathogens with mortality rates approaching 90% for the Zaire subtype. They are also a potential bioterrorism agent. Ebola virus infection causes a severe hemorrhagic disease in humans for which there are no therapeutic treatments nor protective vaccines currently available. For these reasons, Ebola virus is classified as a "category A priority pathogen" by NIH. Expressed on the virus and infected cell surface, the Ebola glycoproteins facilitate entry of the virus into host cells and also interact with the host cells in other important ways. The overall goal of this research program is to thoroughly characterize Ebola glycoprotein-host cell interactions to identify potential targets for therapeutic intervention and also to inform about the basic biology of Ebola replication. This research proposal focuses upon identification and analysis of host factors that interact in with Ebola GP and characterization of how Ebola glycoproteins affect the host cell. The surface glycoprotein (GP) of Ebola plays a key role in entry of the virus into the host and is believed to be responsible for attachment, receptor recognition, and membrane fusion. Definition of the host factors that are required for Ebola entry is essential for comprehending Ebola virus replication and pathogenesis. Endosomal cathepsins are the only currently known cellular factor required for Ebola entry. Specific aim 1 utilizes a series of genetic and biochemical experiments designed to identify important cellular Ebola entry factors. In addition to its function during viral entry, Ebola GP appears to interact with host cells in other important ways. Tetherin/BST-2 is a recently described intrinsic cellular antiviral factor that is active against a number of enveloped viruses and blocks release of mature viral particles. Our recent PNAS manuscript demonstrates that Ebola GP antagonizes the cellular anti-viral factor Tetherin to promote release of Ebola particles. Studies in Specific Aim 2 will examine the requirements for Ebola GP inhibition of this cellular anti-viral factor and will analyze the effects of GP upon Tetherin. In addition to roles in entry and virus release, Ebola GP expression in host cells causes apparent dramatic down modulation of surface proteins leading to loss of cellular adhesion and diminished surface levels of MHC and several other host proteins. Preliminary data suggests a model in which the mucin region in GP acts as a steric shield to block surface accessibility. Testing this model, defining the mechanism of GP-mediated surface protein down-regulation and analyzing the consequences of down- modulation on immune recognition comprise Specific Aim 3 of this proposal. PUBLIC HEALTH RELEVANCE: Ebola viral infection is associated with a high mortality rate and the fear of Ebola infection makes this virus a bioterror concern. There are no effective treatments for Ebola infection. Achieving the Aims of this proposal will significantly enhance our understanding of the Ebola virus glycoproteins (GP) and their interactions with the host and this knowledge can be applied to the design of therapeutics that block GP functions or interfere with Ebola GP-receptor interactions.

描述（由申请人提供）：埃博拉病毒是最致命的人类病原体之一，死亡率接近90％的Zaire亚型。他们也是潜在的生物恐怖剂。埃博拉病毒感染引起人类严重的出血性疾病，目前没有治疗治疗或保护性疫苗。由于这些原因，NIH将埃博拉病毒归类为“优先病原体”。埃博拉蛋白糖蛋白在病毒和感染细胞表面表达，促进该病毒进入宿主细胞，并以其他重要方式与宿主细胞相互作用。该研究计划的总体目标是彻底表征埃博拉蛋白糖蛋白宿主 - 宿主 - 宿主相互作用，以识别治疗干预的潜在靶标，并告知埃博拉病毒的基本生物学。该研究建议着重于鉴定和分析与埃博拉病毒GP相互作用的宿主因素以及埃博拉糖蛋白如何影响宿主细胞的表征。埃博拉病毒的表面糖蛋白（GP）在将病毒进入宿主中起关键作用，被认为负责附着，受体识别和膜融合。埃博拉病毒进入所需的宿主因子的定义对于理解埃博拉病毒复制和发病机理至关重要。内体组织蛋白酶是埃博拉病毒进入所需的唯一已知的细胞因子。特定目标1利用一系列旨在识别重要细胞埃博拉病毒进入因子的遗传和生化实验。除了在病毒进入过程中其功能外，埃博拉病毒GP似乎以其他重要方式与宿主细胞相互作用。 Tetherin/BST-2是最近描述的固有细胞抗病毒因子，其活跃于许多包膜病毒并阻止成熟病毒颗粒的释放。我们最近的PNA手稿表明，埃博拉病毒GP拮抗细胞抗病毒因子Tetherin，以促进埃博拉病毒颗粒的释放。特定目标2中的研究将检查对这种细胞抗病毒因子抑制埃博拉病毒的要求，并将分析GP对Tetherin的影响。除了在进入和病毒释放中的作用外，埃博拉GP在宿主细胞中的表达还会导致表面蛋白的显着下降调节，从而导致细胞粘附的丧失和MHC表面水平降低和其他几种宿主蛋白​​。初步数据提出了一个模型，其中GP中的粘蛋白区域充当阻断表面可及性的空间屏蔽。测试该模型，定义GP介导的表面蛋白下调的机制，并分析下调对免疫识别的后果包括该建议的特定目的3。 公共卫生相关性：埃博拉病毒感染与高死亡率相关，对埃博拉病毒感染的恐惧使该病毒成为生物疗法的关注。没有有效的埃博拉病毒治疗方法。实现该提案的目的将显着增强我们对埃博拉病毒糖蛋白（GP）及其与宿主的相互作用的理解，并且该知识可以应用于阻断GP功能或干扰埃博拉GP受体受体相互作用的治疗剂的设计。