SARS-CoV-2 infection and MHC class I function in bats

蝙蝠中的 SARS-CoV-2 感染和 MHC I 类功能

基本信息

批准号：
10549369
负责人：
PETER CRESSWELL
金额：
$ 20.94万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-11 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10549369
关键词：
2019-nCoV Adaptive Immune System Affect Affinity Antibodies Binding Binding Proteins CD8-Positive T-Lymphocytes CD8B1 gene COVID-19 COVID-19 pandemic Cell Line Cell surface Cells Cessation of life Chiroptera Chronic Complex Coronavirus Coronavirus Infections Dangerousness Dendritic Cells Disease Down-Regulation ERp57 Endoplasmic Reticulum Exposure to Future Generations Globulins Glycoproteins Goals Golgi Apparatus Homologous Protein Human Immune system Immunity Individual Infection Infectious bronchitis virus Innate Immune System Interferons Ion Channel MHC Class I Genes Major Histocompatibility Complex Mediating Monoclonal Antibodies Mus Natural Selections Open Reading Frames Oryctolagus cuniculus Oxidoreductase Peptides Persons Process Property Proteins RNA Viruses Reagent Research Resistance Role SARS-CoV-2 infection Source Sulfhydryl Compounds Surface T cell response T-Lymphocyte TAP1 gene TAP2 gene Testing Time Translations Viral Viral Proteins Virus Writing Yeasts Zoonoses adaptive immunity antigen processing calreticulin cell killing coronavirus pandemic future pandemic gene product glycosylation improved multicatalytic endopeptidase complex nanobodies pandemic disease peptide I polyclonal antibody pressure prevent public health emergency response tapasin targeted treatment

项目摘要

Project Summary COVID-19 is a dangerous pandemic disease caused by the highly infectious coronavirus SARS-CoV-2, which arose by zoonotic transfer from bats. CD8-positive T cells contribute to viral elimination by killing infected cells, preventing viral expansion in an infected individual and limiting the exposure of others to infection. CD8-positive T cells kill virally infected cells by recognizing Major Histocompatibility Complex class I (MHC-I) molecules on their surface that are associated with peptides derived from viral proteins. Like many viruses, SARS-CoV-2 encodes specific proteins that affect surface expression of MHC-I-peptide complexes, resulting in resistance to T cell-mediated killing. We hypothesize that, since SARS-CoV-2 transferred from bats to humans, its MHC-I inhibitory properties evolved in bats. We further hypothesize that, because evolutionary pressure on the virus was mediated by natural selection in the face of chronic exposure to the bat immune system, inhibition of MHC-I function will be more efficient in bats than in humans. Investigating these hypotheses is limited by the lack of appropriate reagents. This proposal seeks to remedy the situation by developing antibodies in mice and rabbits and nanobodies in yeast that identify bat MHC-I proteins as well as the bat equivalents of the additional human gene products that facilitate the generation and surface expression of MHC-I molecules containing bound antigenic peptides, namely TAP1 and TAP2, tapasin, calreticulin and the thiol oxidoreductase ERp57 (PDIA3). As we produce these reagents we will use them to characterize MHC-I-restricted antigen processing in bats and determine how SARS-CoV-2 infection affects it. We have identified four SARS-CoV-2 proteins that independently cause MHC-I down-regulation in humans, and we suggest that these proteins acting in combination are responsible for the reduction in MHC-I surface expression in infected cells. Our goal is to determine whether these gene products, and potentially others, affect the same process in bat cells and how well they do it. Understanding MHC-I function and adaptive immunity in bats will help us to uncover why they are a such potent reservoir for coronaviruses. Determining how bats survive infection by such viruses may suggest targeted therapeutic approaches to improve the ability of humans to resist them and enhance our ability to control and defeat future coronavirus pandemics.

项目概要 COVID-19 是一种由高传染性冠状病毒引起的危险的流行病 SARS-CoV-2，由蝙蝠传播的人畜共患病引起。 CD8 阳性 T 细胞有助于通过杀死受感染的细胞来消除病毒，防止病毒在受感染的个体中扩散，以及限制他人接触感染。 CD8 阳性 T 细胞通过以下方式杀死病毒感染的细胞：识别其表面的主要组织相容性复合物 I 类 (MHC-I) 分子与源自病毒蛋白的肽相关。与许多病毒一样，SARS-CoV-2 编码影响 MHC-I-肽复合物表面表达的特定蛋白质，从而产生抵抗 T 细胞介导的杀伤。我们假设，自从 SARS-CoV-2 转移以来从蝙蝠到人类，其 MHC-I 抑制特性在蝙蝠中进化而来。我们进一步假设因为病毒的进化压力是由自然选择介导的长期接触蝙蝠免疫系统，抑制MHC-I功能会更有效在蝙蝠中比在人类中。由于缺乏适当的证据，调查这些假设受到限制试剂。该提案旨在通过在小鼠体内开发抗体来纠正这种情况兔子和酵母中的纳米抗体可识别蝙蝠 MHC-I 蛋白以及蝙蝠等同物促进产生和表面表达的额外人类基因产物含有结合抗原肽的 MHC-I 分子，即 TAP1 和 TAP2、tapasin、钙网蛋白和硫醇氧化还原酶 ERp57 (PDIA3)。当我们生产这些试剂时，我们将使用它们来表征蝙蝠中 MHC-I 限制性抗原的加工并确定如何 SARS-CoV-2 感染会影响它。我们已经鉴定出四种 SARS-CoV-2 蛋白独立导致人类 MHC-I 下调，我们认为这些蛋白质联合作用导致感染者 MHC-I 表面表达减少细胞。我们的目标是确定这些基因产物以及其他可能的基因产物是否影响蝙蝠细胞中的相同过程以及它们的表现如何。了解 MHC-I 功能和适应性蝙蝠的免疫力将帮助我们揭示为什么它们是冠状病毒如此强大的储存库。确定蝙蝠如何在此类病毒感染下存活下来可能会建议有针对性的治疗提高人类抵抗能力和增强控制能力的方法并战胜未来的冠状病毒大流行。