Administrative Supplement Covid19: Molecular Regulation of B cells and T cells in Human SLE

行政补充 Covid19：人类 SLE 中 B 细胞和 T 细胞的分子调控

• 批准号: 10164943
• 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/10164943
• 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).

COVID19大流行说明了了解人类B细胞对紧急反应的迫切需求 病原体及其在评估牛群免疫中的应用。我们的实验室描述了表型， 人类B细胞反应的不同臂的免疫学和分子特征，尤其是原始的 人类外流体效应子B细胞激活途径的表征及其对不同的贡献 记忆和浆细胞反应。在此基础上，我们建议询问B细胞的不同臂 对SARS-COV-2病毒的反应；确定参与早期，正在进行和 感染后晚期反应；并确定他们对建立牛群免疫的贡献，至少 部分通过保护性B细胞记忆的生成。后者是可能的重要功能 与血清抗体的持久性未偶联；因此，除非正式 测试。我们假设建立细胞B细胞记忆和评估其幅度的能力 质量对于追踪人口的风险至关重要，至关重要。到 设计疫苗能够触发这种保护功能；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感染和康复的血液样本来实现 通过以下特定目的个人：目标1。表征SARS-COV-2特异性B细胞 通过多维B细胞流式细胞仪的反应是细胞来源的精确裁决， 抗SARS-COV-2 B细胞反应的大小和持久性将通过抗原特异性来实现 流式细胞仪，通过多重抗原测定和B细胞群的单细胞分析验证。目的 2。测量SARS-COV-2特异性B细胞记忆和牛群免疫。表型特征和 在AIM 1中建立的抗原特异性流式细胞仪测定法将应用于感染后和晚期 为了理解的时间点：a）SARS-COV-2特异性B细胞存储器的细胞室 居住； b）人口内的质量，大小和分布； c）出处（无论是从早期起 晚期细胞前体）； d）它的一致性或相反，与血清学反应和 长寿命浆细胞（LLPC）的产生。