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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.

项目概要/摘要动物病毒有两个重要特征： a) 将基因组递送至目标的有效系统细胞通常涉及病毒颗粒的激活过程，以及 b) 与适应性免疫相互作用的手段主机的系统。这里详细介绍的结构和生物物理研究将显示诺如病毒如何进化出的衣壳具有这两种功能。全球近五分之一的胃肠炎病例是由人类诺如病毒引起的。诺如病毒每 2-4 年产生新菌株，导致世界范围内的流行病。仅在美国，每年就有约 20 百万病例和超过 70,000 名儿童住院治疗。疫苗的研发工作受到了阻碍缺乏有关抗体结合和抗体逃逸机制的详细结构信息。在此外，该疾病的遏制也存在问题，因为只需十个病毒粒子就足以感染一个正常成人。理解人类诺如病毒的所有这些过程一直很困难，因为缺乏组织培养系统和小动物模型。为此，我们将使用高度易于处理的小鼠诺如病毒系统，我们有细胞培养系统和感染性克隆。关于病毒衣壳的第一个功能，我们提供的证据表明诺如病毒似乎经历了一个明显的激活过程，其中添加胆汁盐会导致突出结构域（P 结构域）旋转并移动约 16Å 到壳表面。这种运动与大大增强有关病毒与细胞的结合。就病毒衣壳的第二个功能而言，我们还提供了证据： P 结构域本身具有高度可塑性，这种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，这里提出的研究不仅将阐明非常独特的诺如病毒激活过程，还包括病毒如何逃避免疫系统。总之，这些信息可以用于未来开发针对这种严重疾病的疫苗和疗法。