Structural, mechanistic, and antigenic insights into the human astrovirus capsid

对人星状病毒衣壳的结构、机制和抗原见解

基本信息

批准号：
10113465
负责人：
Rebecca Michelle DuBois
金额：
$ 7.34万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA CRUZ
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-09 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10113465
关键词：
Affinity Amino Acids Antibodies Antibody titer measurement Antigens Antiviral Therapy Astrovirus Binding Biochemical Biological Assay Biology Blocking Antibodies Capsid Capsid Proteins Cell-Matrix Junction Cells Cellular Assay Child Childhood Crystallization Development Diarrhea Disease Elderly Encephalitis Endocytosis Epitopes Equipment Foundations Genome Genotype Goals Health Human Immunize Immunologics Individual Infection Knowledge Location Measures Molecular Molecular Conformation Mus Patients Play RNA Recombinant Antibody Recombinants Reporting Research Resolution Role Rotavirus Serotyping Severity of illness Site Structure Surface Tertiary Protein Structure Testing Therapeutic Therapeutic antibodies Vaccine Design Vaccine Therapy Vaccines Viral Viral Genome Virion Virus Virus-like particle Work adaptive immune response biophysical analysis brain tissue design enteric pathogen experience extracellular human tissue innovation insight neurotropic neutralizing antibody neutralizing monoclonal antibodies novel novel strategies novel therapeutics prevent skills stool sample vaccine development virology

项目摘要

PROJECT SUMMARY Human astroviruses (HAstV) are a leading cause of viral diarrhea in children. Divergent HAstV strains are associated with fatal human encephalitis. Currently, no vaccines or antiviral therapies exist for HAstV infections. Our goal is to identify sites of vulnerability (Achilles' heels) on the HAstV surface that can be exploited for the development of preventative and therapeutic strategies against HAstV. The HAstV virion is a small, icosahedral virus composed of an RNA genome surrounded by capsid protein. Despite the important role of the HAstV capsid protein in virus entry into host cells, the location of antibody epitopes and the mechanisms of virus-neutralizing antibodies are unknown. Our central hypothesis is that the HAstV capsid spike domain plays a key role in virus entry and is a target of HAstV-neutralizing antibodies. Using a diverse toolbox of structural, biochemical, immunological, and virological approaches, we will pursue three specific aims to (1) use structural and biophysical studies to define HAstV capsid epitopes and serotype-reactivity of a panel of six neutralizing monoclonal antibodies, (2) determine neutralizing mechanisms of a panel of neutralizing monoclonal antibodies targeting the HAstV capsid spike, and define the role of the HAstV capsid spike in cell entry, and (3) determine the structures of the divergent, neurotropic HAstV-VA1 capsid core and spike, test their abilities to elicit neutralizing antibodies, and define HAstV-VA1 neutralizing epitopes. This work represents the first molecular study of HAstV neutralizing epitopes. Results obtained by this work will elucidate mechanisms of HAstV entry and neutralization and provide a foundation for the design of vaccines and therapeutics to prevent and treat HAstV infections.

项目摘要人星座病毒（HASTV）是儿童病毒腹泻的主要原因。分歧hastv菌株是与致命的人脑炎有关。目前，HASTV不存在疫苗或抗病毒疗法感染。我们的目标是在HASTV表面上识别脆弱的位置（阿喀琉斯的高跟鞋）利用用于针对HASTV的预防和治疗策略的发展。 hastv virion是小的，二十体的病毒，由被衣壳蛋白包围的RNA基因组组成。尽管很重要 HASTV衣壳蛋白在病毒进入宿主细胞的作用，抗体表位的位置和病毒中和抗体的机制尚不清楚。我们的中心假设是HASTV CAPSID 尖峰结构域在病毒进入中起关键作用，并且是HASTV中和抗体的靶标。使用多样化结构，生化，免疫学和病毒学方法的工具箱，我们将追求三个特定的特定旨在（1）使用结构和生物物理研究来定义HASTV CAPSID表位和血清型反应性六个中和单克隆抗体的面板，（2）确定一个面板的中和机制中和靶向HASTV CAPSID SPIKE的单克隆抗体，并定义HASTV CAPSID的作用细胞输入中的尖峰，（3）确定发散的神经性hastv-va1 capsid核心的结构尖峰，测试其引起中和抗体的能力，并定义HASTV-VA1中和表位。这项工作代表了HASTV中和表位的首次分子研究。这项工作获得的结果将阐明 HASTV进入和中和的机制，为疫苗的设计提供了基础预防和治疗HASTV感染的治疗剂。