The role of structural plasticity in the norovirus capsid

结构可塑性在诺如病毒衣壳中的作用

基本信息

批准号：
10083180
负责人：
Bernard MONTGOMERY PETTITT
金额：
$ 55.93万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10083180
关键词：
Adaptive Immune System Adopted Adult Affect Animal Model Animals Antibodies Architecture Binding Binding Sites Biochemical Biological Biological Models Blocking Antibodies Capsid Cell Culture System Cell surface Cells Child Complex Containment Cryoelectron Microscopy Crystallization Cues Data Disease Distal Epidemic Epitopes Equilibrium Escape Mutant Family Future Gastroenteritis Genome Genotype Goals Gut Mucosa Herd Immunity Hospitalization Human Immune response Immune system Infection Lagovirus Learning Life Cycle Stages Mediating Methods Molecular Conformation Movement Mucous Membrane Mus Mutagenesis Mutate Mutation Norovirus Play Process Proteins Publishing Rabbit Hemorrhagic Disease Virus Receptor Cell Role Site Sodium Chloride Structure Surface System Testing Therapeutic Tombusvirus Trefoil Motif Vaccines Viral Virion Virus Work bile salts biophysical analysis cell motility design dimer flexibility image reconstruction in silico models and simulation neutralizing antibody receptor receptor binding response simulation structural biology tissue culture vaccine development virology virus development

项目摘要

Project Summary/Abstract Animal viruses share two important features; a) an efficient system for delivering their genome to the target cell usually involving an activation process in the virion and b) a means of interacting with the adaptive immune system of the host. The structural and biophysical studies detailed here will show how the noroviruses have evolved capsids that perform both functions. Human noroviruses are responsible for almost a fifth of all cases of gastroenteritis worldwide. Noroviruses generate new strains every 2-4 years that cause worldwide epidemics. In the US alone, annually there are ~20 million cases and more than 70,000 hospitalizations of children. Efforts for a vaccine have been hindered by a lack of detailed structural information about antibody binding and the mechanisms of antibody escape. In addition, containment of the disease is also problematic since as few as ten virions are sufficient to infect a normal adult. Understanding all of these processes has been difficult with human noroviruses because of the lack of a tissue culture system and small animal model. To this end, we will be using the highly tractable mouse norovirus system where we have a cell culture system and an infectious clone. With regard to the first function of a viral capsid, we present evidence that noroviruses appear to undergo an apparent activation process where the addition of bile salts causes the protruding domain (P domain) to rotated and move ~16Å onto the surface of the shell. This movement is correlated with greatly enhanced binding of the virus to the cell. In terms of the second function of a viral capsid, we also present evidence that the P domain itself is highly plastic and that this motility plays an integral role in receptor binding and antibody escape. Therefore, the studies presented here will not only elucidate a very unique norovirus activation process, but also how the virus evades the immune system. Together, this information could be leveraged in the future to develop vaccines and therapeutics for this serious disease.

项目摘要/摘要动物病毒具有两个重要特征。 a）将其基因组传递到靶标的有效系统细胞通常涉及病毒体中的激活过程，b）与自适应免疫相互作用的一种手段主机的系统。此处详细介绍的结构和生物物理研究将显示北病毒如何具有演变的capsids可以执行这两个功能。人类北病毒造成了全球所有胃炎病例的几乎五分之一。北病毒每2 - 4年产生新的菌株，引起全球流行病。仅在美国，每年有〜20 百万病例和70,000多个儿童住院。疫苗的努力受到了缺乏有关抗体结合和抗体逃脱机制的详细结构信息。在此外，疾病的控制也有问题，因为只有十种病毒就足以感染正常成人。人类诺诺未病毒很难理解所有这些过程，因为缺乏组织培养系统和小动物模型。为此，我们将使用高度的处理小鼠诺如病毒系统，我们有一个细胞培养系统和传染性克隆。关于病毒式衣壳的第一个功能，我们提供了诺如病毒似乎发生的证据一个明显的激活过程，添加胆汁沙拉会导致突出域（P域）旋转并移动〜16Å到壳的表面。这种运动与大大相关病毒与细胞的结合。就病毒式衣壳的第二个功能而言，我们还提供了证据表明 P结构域本身是高度塑性的，并且该运动性在受体结合和抗体中起着不可或缺的作用逃脱。因此，这里介绍的研究不仅将阐明非常独特的诺如病毒激活过程，以及病毒如何逃避免疫系统。在一起，可以利用这些信息开发这种严重疾病的疫苗和治疗的未来。