Structural Basis for T Cell Recognition of SARS-CoV-2

T 细胞识别 SARS-CoV-2 的结构基础

基本信息

  • 批准号:
    10592711
  • 负责人:
  • 金额:
    $ 23.27万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-08-03 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

Project Summary Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the global coronavirus disease 2019 (COVID-19) pandemic. Elucidating the mechanisms underlying the adaptive immune response to SARS-CoV-2 is crucial for predicting vaccine efficacy and assessing the risk of reinfection. Neutralizing antibodies against SARS-CoV-2 have been studied extensively and are clearly protective, but may be short-lived and are not elicited in all infected individuals. Mounting evidence indicates that T cells play a vital role in the clearance of SARS-CoV-2 and in formation of long-term memory responses to this virus. Extensive structural information is now available on neutralizing antibodies from COVID-19 convalescent patients (CPs) bound to the SARS-CoV-2 spike trimer or RBD (>330 PDB entries), resulting in a comprehensive picture of the B cell response to this virus. By contrast, very little structural information is available for SARS-CoV-2-specific TCRs bound to their peptide–MHC (pMHC) targets (4 PDB entries), despite the increasingly appreciated role of T cell-mediated immunity in combatting COVID-19. Our goal is to address this major unmet need by obtaining atomic-level information on SARS-CoV-2 recognition by MHC class I-restricted TCRs from COVID-19 CPs. We will focus on CD8+ T cell epitopes because cytotoxic CD8+ T cells participate directly in viral clearance. Our Specific Aims are: Aim 1: Determine crystal structures of TCR–pMHC complexes. We will target for X-ray crystallographic analysis TCRs specific for epitopes that elicit high levels of TCR expansion in COVID-19 CPs, as well as TCRs associated with protection. To demonstrate feasibility, we have already determined structures of a public and a private TCR from COVID-19 CPs in complex with HLA-A2 and two SARS-CoV-2 spike (S) epitopes, YLQ and RLQ. We will extend these studies to three additional S epitopes (FVF, FQF, RLN) and three nucleocapsid (N) epitopes (LLL, LQL, SPR), which elicit strong T cell responses, and are presented by HLA-A2 or HLA-B7 MHCs. We have diverse panels of TCRs targeting each of these CD8+ T cell epitopes. Aim 2: Analysis of TCR–pMHC structures. TCR–pMHC complex structures determined in Aim 1 will be analyzed using advanced computational structural biology tools to delineate key features of their recognition, as well as the predicted targeting of epitope variants from SARS-CoV-2 and related coronaviruses. These studies will yield foundational knowledge about TCR recognition of SARS-CoV-2 epitopes, about the generation of clonal diversity in epitope-specific TCR repertoires, and about the ways mutations in these epitopes may enable the virus to escape immune surveillance.
项目摘要 严重急性呼吸道综合征冠状病毒2(SARS-CoV-2)是导致全球 2019冠状病毒病(COVID-19)大流行。阐明适应性免疫的机制 对SARS-CoV-2的反应对于预测疫苗效力和评估再感染风险至关重要。 针对SARS-CoV-2的中和抗体已被广泛研究,并且显然具有保护作用,但可能 是短暂的,并不是在所有受感染的个体中引起的。越来越多的证据表明,T细胞在免疫系统中起着至关重要的作用。 在清除SARS-CoV-2和形成对这种病毒的长期记忆反应中发挥作用。广泛 现在可以获得COVID-19康复期患者(CP)中和抗体的结构信息 结合到SARS-CoV-2刺突三聚体或RBD(>330 PDB条目),从而全面了解 B细胞对这种病毒的反应。相比之下,SARS-CoV-2特异性的结构信息非常少。 TCR与其肽-MHC(pMHC)靶标结合(4个PDB条目),尽管TCR的作用越来越受到重视, T细胞介导的免疫力对抗COVID-19。我们的目标是通过以下方式解决这一主要未满足的需求: 来自COVID-19 CP的MHC I类限制性TCR识别SARS-CoV-2的原子级信息。我们 将集中在CD 8 + T细胞表位,因为细胞毒性CD 8 + T细胞直接参与病毒清除。我们 具体目标是: 目的1:确定TCR-pMHC复合物的晶体结构。我们会用X光 晶体学分析对引起COVID-19 CP中高水平TCR扩增的表位具有特异性的TCR, 以及与保护相关的TCR。为了证明可行性,我们已经确定了 来自与HLA-A2复合的COVID-19 CP的公共和私人TCR和两个SARS-CoV-2峰值(S) 表位,YLQ和RLQ。我们将这些研究扩展到三个额外的S表位(FVF,BVF,RLN)和三个 核衣壳(N)表位(LLL、LQL、SPR),其引起强烈的T细胞应答,并由HLA-A2呈递 或HLA-B7 MHC。我们具有靶向这些CD 8 + T细胞表位中的每一个的不同TCR组。 目的2:分析TCR-pMHC的结构。目标1中确定的TCR-pMHC复合物结构将 使用先进的计算结构生物学工具进行分析,以描述其识别的关键特征, 以及来自SARS-CoV-2和相关冠状病毒的表位变体的预测靶向。 这些研究将产生关于TCR识别SARS-CoV-2表位的基础知识, 表位特异性TCR库中克隆多样性的产生,以及这些TCR库中突变的方式, 表位可能使病毒逃避免疫监视。

项目成果

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Roy A Mariuzza其他文献

Roy A Mariuzza的其他文献

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{{ truncateString('Roy A Mariuzza', 18)}}的其他基金

Structure, Function and Mechanistic Analysis of LAG3
LAG3的结构、功能及机理分析
  • 批准号:
    10542350
  • 财政年份:
    2019
  • 资助金额:
    $ 23.27万
  • 项目类别:
Structure, Function and Mechanistic Analysis of LAG3
LAG3的结构、功能及机理分析
  • 批准号:
    10317043
  • 财政年份:
    2019
  • 资助金额:
    $ 23.27万
  • 项目类别:
Structure, Function and Mechanistic Analysis of LAG3
LAG3的结构、功能及机理分析
  • 批准号:
    10078854
  • 财政年份:
    2019
  • 资助金额:
    $ 23.27万
  • 项目类别:
Structure and Activation of a Multiprotein Signaling Complex
多蛋白信号复合物的结构和激活
  • 批准号:
    10238118
  • 财政年份:
    2017
  • 资助金额:
    $ 23.27万
  • 项目类别:
Structure and Activation of a Multiprotein Signaling Complex
多蛋白信号复合物的结构和激活
  • 批准号:
    9752433
  • 财政年份:
    2017
  • 资助金额:
    $ 23.27万
  • 项目类别:
Structure and Activation of a Multiprotein Signaling Complex
多蛋白信号复合物的结构和激活
  • 批准号:
    9448073
  • 财政年份:
    2017
  • 资助金额:
    $ 23.27万
  • 项目类别:
Structural Analysis of the TCR-CD3 Complex and TCR Signaling
TCR-CD3 复合物和 TCR 信号传导的结构分析
  • 批准号:
    9251684
  • 财政年份:
    2016
  • 资助金额:
    $ 23.27万
  • 项目类别:
Structural Analysis of the TCR-CD3 Receptor Complex
TCR-CD3 受体复合物的结构分析
  • 批准号:
    8512173
  • 财政年份:
    2013
  • 资助金额:
    $ 23.27万
  • 项目类别:
Structural Analysis of the TCR-CD3 Receptor Complex
TCR-CD3 受体复合物的结构分析
  • 批准号:
    8605510
  • 财政年份:
    2013
  • 资助金额:
    $ 23.27万
  • 项目类别:
Solution structure and dynamics of TCR in free and peptide-MHC-bound states
游离状态和肽 MHC 结合状态下 TCR 的溶液结构和动力学
  • 批准号:
    8301177
  • 财政年份:
    2012
  • 资助金额:
    $ 23.27万
  • 项目类别:

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