HBGA receptors in host cell entry and infection of norovirus

HBGA受体在诺如病毒进入宿主细胞和感染中的作用

基本信息

批准号：
9182813
负责人：
Wen Jiang
金额：
$ 48.98万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9182813
关键词：
Alpha Cell Antibodies Antigen Receptors Antiviral Agents Binding Biological Assay Biological Models Blood Group Antigens Caliciviridae Calicivirus Capsid Capsid Proteins Carbohydrates Cell Culture Techniques Cell Line Cells Collaborations Confined Spaces Cryoelectron Microscopy Disease Outbreaks Economics Evaluation Family Food Contamination Gastroenteritis Genetic Genome Goals Health Health care facility Hospitals Hot Spot Human Infection Kinetics Knowledge Laboratories Life Cycle Stages Link Mediating Membrane Modeling Molecular Molecular Conformation Molecular Virology Monitor Mucins Mutagenesis Mutation Norovirus Pathogenesis Pathway interactions Penetration Persons Play Population Predisposition Primates Procedures Process Public Health RNA Reagent Research Resolution Reverse Transcriptase Polymerase Chain Reaction Role Saliva Schools Site Societies Structure System Testing Time United States Vertebral column Viral Viral Genome Virion Virus Virus Diseases Virus Replication Water antigen binding base experimental study flexibility genomic RNA improved novel operation pandemic disease particle pathogen permissiveness public health relevance receptor reverse genetics screening structural biology viral RNA virus culture virus host interaction

项目摘要

DESCRIPTION (provided by applicant): We seek to understand the interactions between Human noroviruses (HuNoVs) and their Histo-blood group antigen (HBGA) receptors in the attachment/penetration into host cells and potentially triggering conformational dynamics of the viral capsid and genome release in the early stage of viral infection. HuNoVs in the Caliciviridae family are the major cause of nonbacterial gastroenteritis worldwide. The highly contagious HuNoVs can rapidly spread among the population through contaminated food, water and person-to-person contact in confined spaces, such as cruises, hotels, schools, hospitals and other long-term health care facilities. There are approximately 21 million cases of infection in ~1,500 HuNoVs outbreaks in the United States annually, which causes severe economic loss to society and threatens human health. Despite this serious public health concern, knowledge about the infection mechanism and pathogenesis of HuNoVs is limited due to the lack of a permissive cell line. Our past decade studies showed a strong association of HBGAs as a susceptibility factor in NoV infection, and therefore further studies to seek direct evidence on HBGAs as a receptor of NoVs are necessary. In this R01 application, we will use the recently discovered primate Tulane virus (TV) as the model system to fulfill our goals because of its close genetic and structural similarities to HuNoVs, the availability of an established cultivation system, and the fact that TV also utilizes HBGAs as receptors. We will first test the HBGA requirement in TV infection in cell cultures by performing blocking or inhibition experiments using HBGA-specific blocking reagents. We also will study the roles of HBGAs in the attachment and/or penetration of TV entry into host cells. Furthermore, we will test a novel hypothesis of HBGA-triggered dynamic change of TV capsid on viral genome release to initiate infection. This hypothesis is based on our recent observation of conformational changes of TV following interaction with HBGAs. Finally, we will validate these findings using a reverse genetic system of TV by mutagenesis studies in attempt to determine the hot spots in the capsid protein responsible for these interactions. We also aim to develop the TV culture system into a useful surrogate for antiviral screening/evaluation against HuNoVs. The proposed studies in this application will be performed by collaboration between two research teams on structural biology (Wen Jiang, PI) and molecular virology (Xi Jiang, co-PI) with an excellent collaboration track record in the past. We are confident that we will make a rapid progress in fulfilling our aims.

描述（由申请人提供）：我们试图了解人类诺诺病毒（Hunovs）及其在附着/穿透宿主细胞中的组织血液组抗原（HBGA）受体之间的相互作用，并潜在地触发病毒感染早期阶段的病毒capsID和基因组释放的构象动力学。 Caliciviridae家族中的Hunovs是全球非细菌胃炎的主要原因。具有污染的食物，水和人与人之间的接触，例如巡航，酒店，学校，医院和其他长期医疗保健设施，可以通过受污染的食物，水和人与人接触来迅速在人群之间传播。在美国，大约有2100万例感染案件在约1,500次霍诺夫爆发中，这会给社会带来严重的经济损失并威胁人类健康。尽管存在严重的公共卫生问题，但由于缺乏宽松的细胞系，人们对霍诺夫的感染机制和发病机理的知识受到限制。我们过去的十年研究表明，HBGA是Nov感染中易感因素的密切相关性，因此需要进一步的研究以直接证明HBGA作为NOV的受体。在此R01应用程序中，我们将使用最近发现的灵长类动物杜兰病毒（TV）作为模型系统来实现我们的目标，因为它与霍诺夫斯的遗传和结构相似，可用性已建立了培养系统，电视还利用HBGA作为受体这一事实。我们将通过使用HBGA特异性阻断试剂进行阻断或抑制实验，首先测试细胞培养物中电视感染中的HBGA需求。我们还将研究HBGA在电视进入宿主细胞的附着和/或穿透中的作用。此外，我们将检验一个新的假设，即在病毒基因组释放中受HBGA触发的电视帽动态变化以启动感染。该假设是基于我们最近观察到与HBGA相互作用后电视构象变化的观察。最后，我们将通过诱变研究使用TV的反向遗传系统来验证这些发现，以确定负责这些相互作用的衣壳蛋白中的热点。我们还旨在将电视培养系统发展为有用的替代抗病毒筛查/评估Hunovs。该应用程序中提出的研究将通过两个关于结构生物学（Wen Jiang，Pi）和分子病毒学（Xi Jiang，co-Pi）的研究团队之间的合作进行，过去曾与过去的合作记录出色。我们有信心我们将在实现目标方面取得迅速的进步。