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A Secreted Viral Protein Determines Norovirus Persistence By Immune Evasion

分泌的病毒蛋白通过免疫逃避决定诺如病毒的持久性

基本信息

批准号：
10219936
负责人：
Sanghyun Lee
金额：
$ 24.5万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10219936
关键词：
Advisory Committees Antibodies Biological Models Biology Capsid Caspase Cell Line Cells Cellular Tropism Childhood Cleaved cell Clustered Regularly Interspaced Short Palindromic Repeats Cultured Cells Cytomegalovirus Data Defect Development Development Plans Diamond Disease Outbreaks Doctor of Philosophy Educational workshop Epithelial Epithelial Cells Exhibits Extracellular Space Faculty Gastroenteritis Genes Genetic Genetic study Goals Grant Growth Human Immune Evasion Immune system Immunity Immunize In Vitro Infection Interferons Interview Intracellular Space Knock-out Korea Mediating Membrane Proteins Mentors Mentorship Modeling Molecular Mus Myeloid Cells Nonstructural Protein Norovirus Occupational activity of managing finances Passive Immunity Patients Physiological Point Mutation Positioning Attribute Postdoctoral Fellow Prevention Production Protein Precursors Proteins Recombinants Research Research Personnel Research Project Grants Research Proposals Science Signal Transduction Site System Testing Therapeutic Time Training Activity Tropism Universities Vaccination Vaccines Viral Viral Proteins Virulence Virus Washington Work Writing career career development combinatorial cytokine diarrheal disease enteric infection expression vector foodborne illness improved in vivo in vivo Model inhibitor/antagonist intestinal epithelium intraperitoneal macrophage medical schools mutant novel novel vaccines prevent response screening skills therapeutic development vaccine candidate vaccine development virus host interaction

项目摘要

Project Summary/Abstract This proposal describes a four year career development plan and a research strategy for Dr. Sanghyun Lee to transition from a postdoctoral fellow to an independent academic faculty position investigating virus-host interactions. The overall research goal of the proposal is to elucidate the mechanism by which a secreted viral non-structural protein antagonizes host immunity, and to evaluate this viral factor as a novel vaccine target. Candidate: I have focused my science career on understanding virus and host interactions at both molecular and physiological levels. In my Ph.D. work with Dr. Kwangseog Ahn at Seoul National University in Korea, I worked on understanding the virulence of human cytomegalovirus (HCMV), and specifically focused on the factors contributing to HCMV virulence in human patients. As a postdoc in Dr. Skip Virgin's lab at Washington University School of Medicine, I studied the cellular tropism of norovirus and the key host immune system determinants controlling norovirus infection in the gut. Career Development Plan: In addition to the research proposal outlined here, I will devote approximately 15% of my time to training activities. I will continue my professional development under the guidance of my mentor Dr. Virgin's and my co-mentor Dr. Gaya Amarasinghe. I have assembled a career advisory committee composed of Dr. Michael Diamond, Dr. Megan Baldridge, and Dr. Haina Shin that will evaluate and facilitate my research progress and transition to independence. Beyond these training activities, I will prepare to transition to an independent faculty position by improving grant-writing and interviewing skills through workshops at WUSM, and begin planning for the new financial, management, and mentorship responsibilities of an independent investigator. Research Project: Human noroviruses (HNoVs) are the leading global cause of gastroenteritis. However, there are no approved vaccines or therapeutics. With Murine norovirus (MNoV) model, we identified Tuft cells, a rare type of intestinal epithelial cell (IEC), as the reservoir for MNoV fecal shedding and persistence. Genetic studies revealed that viral non-structural protein NS1, rather than a viral surface protein, is the determinant of Tuft cell tropism, and interferon-lambda (IFN-λ) to be a key host determinant. Our preliminary data suggests that the NS1 protein is cleaved by host caspase(s) and secreted into the extracellular space, and NS1 blocks IFN-λ production. Therefore, we hypothesize that secreted NS1 protein antagonizes IFN-λ production, and that this antagonism is the key determinant of in vivo Tuft cell tropism. The long-term goal of this study is to understand the molecular mechanism of NS1 secretion and IFN-λ immune evasion by MNoV, and to apply our findings to evaluate secreted NS1 as a candidate for vaccine and therapeutic development in humans.

项目总结/摘要这份建议书描述了一个四年的职业发展计划和一个研究战略，李从博士后研究员过渡到独立的学术教师职位，研究病毒宿主交互.该提案的总体研究目标是阐明分泌型病毒非结构蛋白拮抗宿主免疫，并评估这种病毒因子作为新的疫苗靶点。候选人：我的科学生涯主要集中在理解病毒和宿主在分子水平上的相互作用，和生理水平。在我的博士学位上。我和韩国首尔国立大学的Kwangseog Ahn博士一起工作，致力于了解人类巨细胞病毒（HCMV）的毒力，并特别关注在人类患者中促进HCMV毒力的因素。作为华盛顿斯基普·维珍博士实验室的博士后在大学医学院，我研究了诺如病毒的细胞嗜性和关键宿主免疫系统控制肠道中诺如病毒感染的决定因素。职业发展计划：除了这里概述的研究建议，我将投入大约15% 我的时间训练活动。我将在导师的指导下继续我的专业发展博士维珍和我的导师加亚·阿马拉辛格博士我召集了一个职业顾问委员会由Michael Diamond博士、Megan Baldridge博士和Haina Shin博士组成，将评估和促进我的研究进展和向独立的过渡。除了这些培训活动，我还将准备过渡到一个独立的教师职位，通过提高赠款写作和面试技巧，在WUSM举办研讨会，并开始规划新的财务、管理和指导职责一个独立的调查员。研究项目：人类诺如病毒（HNoV）是全球胃肠炎的主要原因。然而，在这方面，没有批准的疫苗或治疗剂。利用小鼠诺如病毒（MNoV）模型，我们鉴定了Tuft细胞，一种罕见类型的肠上皮细胞（IEC），作为MNoV粪便脱落和持久性的储存库。遗传研究表明，病毒的非结构蛋白NS 1，而不是病毒的表面蛋白，是决定性的，簇细胞嗜性，干扰素-λ（IFN-λ）是一个关键的主机决定因素。我们的初步数据显示 NS 1蛋白被宿主半胱天冬酶切割并分泌到细胞外空间， IFN-λ产生。因此，我们假设分泌的NS 1蛋白拮抗IFN-λ的产生，这种拮抗作用是体内簇细胞向性的关键决定因素。这项研究的长期目标是了解MNoV分泌NS 1和IFN-λ免疫逃逸的分子机制，并应用我们的研究成果，研究结果评估分泌的NS 1作为人类疫苗和治疗开发的候选者。