Principal Project

主要项目

• 批准号: 10198495
• 负责人: Ignacio E. Sanz
• 金额: $ 52.56万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-06 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198495
• 关键词: 2019-nCoV; Address; Administrative Supplement; Affinity; Antibodies; Antibody Response; Antigens; Aspirate substance; Autoimmune Diseases; Autoimmunity; B-Cell Activation; B-Lymphocytes; Biological Assay; Blood specimen; Bone Marrow; COVID-19; COVID-19 pandemic; Cell Compartmentation; Cells; Cellular Assay; Clinical Trials; Communities; Complement; Coronavirus; Development; Diagnostic tests; Disease; Exposure to; Flow Cytometry; Funding; General Population; Generations; Genetic Transcription; Goals; Grant; Herd Immunity; Human; Immune response; Immunologic Memory; Immunologics; Individual; Infection; Investigation; Knowledge; Laboratories; Laboratory Diagnosis; Link; Longevity; Measurement; Measures; Medical; Memory; Memory B-Lymphocyte; Molecular; Molecular Evolution; Monoclonal Antibodies; Mus; National Institute of Allergy and Infectious Disease; Parents; Pathway interactions; Patients; Phase; Phenotype; Plasma Cells; Population; Regulation; Resolution; Risk; Serological; Serum; Systemic Lupus Erythematosus; T-Lymphocyte; TLR7 gene; Testing; Therapeutic Monoclonal Antibodies; Time; U-Series Cooperative Agreements; United States National Institutes of Health; Vaccine Design; Vaccines; Viral; Virus; Work; acute infection; adjudication; arm; base; clinical Diagnosis; cross reactivity; neutralizing monoclonal antibodies; pathogen; response; single cell analysis; vaccine development

The COVID19 pandemic illustrates the urgent need for understanding human B cell responses to emergent pathogens and its application to assessing herd immunity. Our laboratories have described the phenotypic, immunological and molecular features of different arms of human B cell responses and in particular, the original characterization of the human extrafollicular effector B cell activation pathway and its contribution to different memory and plasma cells responses. On that basis, we we propose to interrogate the different arms of the B cell response to the SARS-CoV-2 virus; to identify the B cell compartments that participate in the early, ongoing and late post-infection responses; and to determine their contribution to the establishment of herd immunity, at least in part through the generation of protective B cell memory. The latter is an essential feature that could be uncoupled from the persistence of serum antibodies; and therefore, would go unrecognized unless formally tested. We postulate that the establishment of cellular B cell memory and the ability to evaluate its magnitude and quality will be critical to track the risk of the population to short-term re-infection and seasonal exposure; to design vaccines capable to trigger this protective feature; and to develop SARS-CoV-2 B cell-based diagnostic tests. These goals will be accomplished using blood samples from SARS-CoV-2-infected and convalescent individuals through the following specific aims: Aim 1. Characterization of SARS-CoV-2-specific B cell responses through multidimensional B cell flow cytometry A precise adjudication of the cellular origin, magnitude, and persistence of the anti-SARS-CoV-2 B cell response will be accomplished by antigen-specific flow cytometry and validated by multiplex antigen assays and single cell analysis of the B cell populations. Aim 2. Measurement of SARS-CoV-2-specific B cell memory and herd immunity. Phenotypic features and antigen-specific flow cytometry assays established in aim 1, will be applied to intermediate and late post-infection time points in order to understand: a) the cellular compartments in which SARS-CoV-2-specific B cell memory resides; b) its quality, magnitude and distribution within the population; c) its provenance (whether from early of late cellular precursors); and d) its concordance or conversely, uncoupling from serological responses and the generation of long-lived plasma cells (LLPC).

新冠病毒大流行表明迫切需要了解人类 B 细胞对突发事件的反应 病原体及其在评估群体免疫力中的应用。我们的实验室已经描述了表型， 人类 B 细胞反应不同分支的免疫学和分子特征，特别是原始 人滤泡外效应 B 细胞激活途径的表征及其对不同 记忆和浆细胞反应。在此基础上，我们建议探究 B 细胞的不同臂 对 SARS-CoV-2 病毒的反应；识别参与早期、正在进行和 感染后反应迟缓；并确定它们对建立群体免疫的贡献，至少 部分是通过保护性 B 细胞记忆的生成。后者是一个基本特征，可以 与血清抗体的持续存在无关；因此，除非正式 已测试。我们假设细胞 B 细胞记忆的建立以及评估其大小的能力 质量对于追踪人群短期再次感染和季节性暴露的风险至关重要；到 设计能够触发这种保护功能的疫苗；并开发基于 SARS-CoV-2 B 细胞的诊断 测试。这些目标将使用来自 SARS-CoV-2 感染者和康复者的血液样本来实现 目标 1. SARS-CoV-2 特异性 B 细胞的表征 通过多维 B 细胞流式细胞术进行反应对细胞起源的精确判断， 抗 SARS-CoV-2 B 细胞反应的强度和持久性将通过抗原特异性来实现 流式细胞术并通过多重抗原测定和 B 细胞群的单细胞分析进行验证。目的 2. SARS-CoV-2 特异性 B 细胞记忆和群体免疫的测量。表型特征和 目标 1 中建立的抗原特异性流式细胞术检测将应用于感染后的中期和晚期 时间点，以便了解：a) SARS-CoV-2 特异性 B 细胞记忆的细胞区室 居住； b) 其质量、规模和在人群中的分布； c) 其出处（无论是从早期 晚期细胞前体）； d) 其一致性或相反，与血清学反应和 长寿命浆细胞（LLPC）的产生。