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
- 来源:
- 关键词:2019-nCoVAddressAgammaglobulinemiaAntibodiesAntibody ResponseB-LymphocytesBindingCD8-Positive T-LymphocytesCOVID-19COVID-19 pandemicCOVID-19 vaccineCellular ImmunityComplexCoronavirusDatabasesDepositionDiseaseEpitopesGenerationsGenesGoalsGrantHLA-A geneHLA-A2 AntigenHLA-B AntigensHLA-B7 AntigenImmuneImmunityImmunologic SurveillanceIndividualInfectionInfluenza A virusKnowledgeLymphopeniaMHC Class I GenesMediatingModelingMolecularMutagenesisMutationNucleocapsidPatientsPeptide/MHC ComplexPharmacologic SubstancePlayPrivatizationRecoveryResolutionRespiratory SystemRespiratory syncytial virusRisk AssessmentRoentgen RaysRoleSARS-CoV-2 antibodySARS-CoV-2 variantSeverity of illnessStructureT cell responseT memory cellT-Cell ActivationT-Cell ReceptorT-LymphocyteT-Lymphocyte EpitopesT-cell receptor repertoireTestingTimeVaccine DesignVariantViralViral Respiratory Tract InfectionVirusX-Ray Crystallographyadaptive immune responsecomputerized toolscross reactivitycytotoxic CD8 T cellsdesignexperienceinsightlong term memorymolecular sequence databaseneutralizing antibodynovelreceptor bindingresponsestructural biologythree dimensional structuretooluniversal coronavirus vaccinevaccine efficacy
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
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Roy A Mariuzza其他文献
Roy A Mariuzza的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 23.27万 - 项目类别:
Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 23.27万 - 项目类别:
Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 23.27万 - 项目类别:
Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 23.27万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 23.27万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 23.27万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 23.27万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 23.27万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 23.27万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 23.27万 - 项目类别:
Research Grant