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

• 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
• 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

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.

项目总结/摘要 动物病毒共有两个重要特征：a）将其基因组递送至靶标的有效系统 细胞，通常涉及病毒体中的活化过程，和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 进化出了同时具有这两种功能的衣壳。 人类诺如病毒造成了全球近五分之一的胃肠炎病例。诺如病毒 每2-4年产生新的菌株，导致全球流行。仅在美国，每年就有约20起 2000万个病例和7万多名儿童住院治疗。研制疫苗的努力受到了 缺乏关于抗体结合和抗体逃逸机制的详细结构信息。在 此外，控制这种疾病也是有问题的，因为只要十个病毒体就足以感染一个人。 正常的成年人对于人类诺如病毒，理解所有这些过程是困难的，因为 缺乏组织培养体系和小动物模型。为此，我们将使用高度易处理的 小鼠诺如病毒系统，我们有一个细胞培养系统和一个感染性克隆。 关于病毒衣壳的第一个功能，我们提出的证据表明，诺如病毒似乎经历 表观活化过程，其中加入胆汁盐导致突出结构域（P结构域） 旋转并在外壳表面上移动~ 16度。这种运动与大大增强的 病毒与细胞的结合。关于病毒衣壳的第二个功能，我们也提供了证据， P结构域本身是高度可塑性，这种运动性在受体结合和抗体中起着不可或缺的作用 逃跑因此，这里提出的研究不仅将阐明一个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。总之，这些信息可以用于 为这种严重的疾病开发疫苗和治疗方法。