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

• 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
• 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

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.

项目摘要 COVID-19是一种由高度传染性冠状病毒引起的危险的大流行性疾病 SARS-CoV-2，由蝙蝠的人畜共患病转移引起。CD 8阳性T细胞有助于 通过杀死受感染细胞消除病毒，防止病毒在受感染个体中扩增， 限制其他人接触感染。CD 8阳性T细胞通过以下方式杀死病毒感染的细胞： 识别其表面上的主要组织相容性复合物I类（MHC-I）分子， 与来自病毒蛋白的肽有关。像许多病毒一样，SARS-CoV-2 编码影响MHC-I-肽复合物表面表达的特定蛋白质， 抵抗T细胞介导的杀伤。我们假设，由于SARS-CoV-2转移到 从蝙蝠到人类，它的MHC-I抑制特性在蝙蝠中进化。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， 长期暴露于蝙蝠免疫系统，抑制MHC-I功能将更有效 而不是人类。调查这些假设受到缺乏适当的限制 试剂这项提议试图通过在小鼠中开发抗体来补救这种情况， 兔子和酵母中的纳米抗体识别蝙蝠MHC-I蛋白以及蝙蝠等同物 促进产生和表面表达的其他人类基因产物 含有结合的抗原肽，即TAP 1和TAP 2，tapasin， 钙网蛋白和硫醇氧化还原酶ERp 57（PDIA 3）。当我们生产这些试剂时， 用它们来描述蝙蝠中MHC-I限制性抗原的加工过程， 我们已经鉴定了四种SARS-CoV-2蛋白， 在人类中独立引起MHC-I下调，我们认为这些蛋白质 联合作用导致受感染细胞中MHC-I表面表达的减少。 细胞我们的目标是确定这些基因产物，以及潜在的其他基因产物，是否影响了 了解MHC-I的功能和适应性 蝙蝠的免疫力将帮助我们揭示为什么它们是冠状病毒的强大宿主。 确定蝙蝠如何在感染此类病毒后存活可能会提出有针对性的治疗方法 提高人类抵抗它们的能力和增强我们控制它们的能力的方法 并战胜未来的冠状病毒大流行。