Low pH-mediated HSV fusion and entry

低 pH 介导的 HSV 融合和进入

基本信息

批准号：
9067982
负责人：
ANTHONY V NICOLA
金额：
$ 37.75万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-15 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9067982
关键词：
Acids Address Antiviral Agents Baculoviruses Biochemistry Biological Assay Blindness Cell fusion Cell surface Cells Cellular biology Chimeric Proteins Complex Data Development Disease Encephalitis Epithelial Cells Event Experimental Designs Glycosaminoglycans Goals Health Herpes Labialis Herpesviridae Herpesviridae Infections Human Immunocompromised Host In Vitro Infection Intervention Knowledge Link Mediating Mediator of activation protein Membrane Fusion Modeling Molecular Molecular Conformation Molecular Virology Morbidity - disease rate Mutagenesis Neonatal Outcome Pathway interactions Play Process Protein Family Proteins Recurrence Regulation Research Rhabdoviridae Role Sexually Transmitted Diseases Shapes Simplexvirus Site Structure Surface Techniques Testing Time Viral Viral Fusion Proteins Virion Virus Virus Diseases base cell type env Gene Products genital infection inhibitor/antagonist latent infection member mortality novel novel strategies pathogen prevent receptor receptor binding shift work virus envelope virus virus interaction

项目摘要

DESCRIPTION (provided by applicant): Herpes simplex virus (HSV) causes lifelong latent infections in humans. It is responsible for significant disease, ranging from cold sores and genital infections to blindness and fatal encephalitis. The long- term goal of this project is to understand the molecular mechanisms that HSV uses to gain entry into host cells. An emerging concept in herpesvirology is that endosomal pH of the host cell is required for viral entry, often in a cell type specific manner. However, the mechanistic role that low pH plays in herpes viral entry is not clear. HSV utilizes a low pH, endocytic pathway for infection of epithelial cells, the primary portal of entry into the human host and the site of recurrent infection. HSV gB belongs to the class III viral fusion protein family, whose members also drive the entry several other important enveloped viruses. The class III fusion mechanism remains poorly defined. The focus of this proposal is the delineation of the mechanism of low pH membrane fusion mediated by HSV. Based on previous results and our new preliminary studies, we have formulated three specific aims. In Specific Aim # 1, we will elucidate viral and cellular parameters of HSV membrane fusion triggered by low pH. We will reveal critical regions of the fusion protein gB and define the roles of cellular receptors in cell-cell fusion triggered by low pH. In Aim 2, we will delineate a novel role for an HSV envelope protein, not previously associated with fusion and entry. We will elucidate its importance for conformational changes triggered by acidic pH. For Aim 3, we will determine the functional consequences of the interaction between HSV gH/gL and gB in the context of low pH fusion and entry. Our experimental design employs techniques of molecular virology, biochemistry and cell biology. Achieving these aims will fill critical knowledge gaps about how the complex fusion mechanism of herpesviruses is triggered by host intravesicular pH in physiologically relevant cell types. The results will represent significant advances in our understanding of class III fusion mechanisms, and may aid in development of novel, antiviral interventions.

描述（由适用提供）：单纯疱疹病毒（HSV）引起人类的终生潜在感染。它是导致重大疾病的原因，从唇疱疹和生殖器感染到失明和致命脑炎。该项目的长期目标是了解HSV用于进入宿主细胞的分子机制。疱疹病毒学中的一个新兴概念是，宿主细胞的内体pH是病毒细胞所必需的，通常是特定于细胞类型的方式。但是，低pH在病毒进入中发挥的机械作用尚不清楚。 HSV利用低pH，内吞途径来感染上皮细胞，主要进入人类宿主和复发感染部门的门户。 HSV GB属于III类病毒融合蛋白家族，其成员也将入口驱动其他几种重要的包围病毒。 III类融合机制的定义仍然很差。该提案的重点是描述由HSV介导的低pH膜融合机理。根据先前的结果和我们的新初步研究，我们制定了三个具体目标。在特定的目标＃1中，我们将阐明由低pH触发的HSV膜融合的病毒和细胞参数。我们将揭示融合蛋白GB的关键区域，并定义细胞接收器在低pH触发的细胞融合中的作用。在AIM 2中，我们将描述HSV包膜蛋白的新作用，以前与融合和进入相关。我们将阐明其对由酸性pH触发的构象变化的重要性。对于AIM 3，我们将在低pH融合和进入的背景下确定HSV GH/GL和GB之间相互作用的功能后果。我们的实验设计员工分子病毒学，生物化学和细胞生物学技术。实现这些目标将填补有关疱疹病毒的复杂融合机制如何由宿主在物理相关的细胞类型中触发的关键知识差距。结果将代表我们对III类融合机制的理解，并可能有助于开发新型的抗病毒干预措施。