Protective and Pathogenic T Cells Responding to SARS-CoV-2 in Health and Disease

健康和疾病中对 SARS-CoV-2 做出反应的保护性和致病性 T 细胞

• 批准号: 10218954
• 负责人: Judith A Woodfolk
• 金额: $ 24.23万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-13 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218954
• 关键词: 2019-nCoV; Acute; Address; Admission activity; Adult; Algorithms; Antibodies; Antibody Formation; Antibody Response; Antigens; Antiviral Agents; Antiviral Response; Asthma; B-Lymphocytes; Benign; Biological Markers; CD4 Positive T Lymphocytes; COVID-19; COVID-19 monitoring; COVID-19 pandemic; COVID-19 patient; COVID-19 vaccine; CXCL10 gene; Cell Count; Cells; Chemotactic Factors; Common Cold; Coronavirus; Coupled; Critical Illness; Cues; Data; Disease; Epitopes; Exposure to; Flow Cytometry; Gene Expression; Health; Human; Immune; Immune Tolerance; Immunity; Immunoglobulin G; In Vitro; Individual; Infection; Inflammatory; Interferon Type II; Interleukin-6; Knowledge; Link; Maps; Memory; Methods; Modeling; Molecular Profiling; Monitor; Nature; Outcome; Outcome Study; Pathogenicity; Patients; Peptides; Phase; Phenotype; Plasma; Production; Proteome; Resources; Respiratory Failure; Respiratory System; Rhinovirus; Rhinovirus infection; Risk; Risk Factors; Role; SARS-CoV-2 immunity; Sampling; Seminal; Serum; Shock; Specificity; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Epitopes; TNF gene; Testing; Vaccine Design; Vaccines; Viral; Viral Pathogenesis; Virus; Virus Diseases; Work; adaptive immunity; airway inflammation; analytical method; analytical tool; antiviral immunity; asthmatic; base; biomarker panel; computerized tools; coronavirus disease; cross reactivity; cytokine; cytokine release syndrome; experience; high dimensionality; in silico; in vivo; infection rate; insight; lung injury; man; memory CD4 T lymphocyte; mortality; neutralizing antibody; new therapeutic target; novel; novel coronavirus; pulmonary function; respiratory virus; response; severe COVID-19; theories; tool

SUMMARY Understanding the adaptive response to SARS-CoV-2 is critical to halting the devastation wreaked by the COVID-19 pandemic, by identifying new drug targets and informing the rational design of vaccines. Common coronaviruses and human rhinovirus (RV) both cause common cold, and multiple strains of each exist that have varying degrees of sequence identity. All humans, and adults in particular, possess antigen-experienced immune cells by virtue of frequent viral infections. Our work using experimental infections with RV in man has provided unprecedented insight into adaptive immunity to this relatively benign, but troublesome, virus. Seminal findings include a pivotal role for the rapid mobilization of cross-reactive memory T helper 1 (Th1) cells and T-bet+ B cells in controlling RV infection. Th1 cells are critical to anti-viral responses by aiding in viral clearance through secretion of IFN-γ, and providing help to B cells for the production of neutralizing antibodies. Notably, expansion of circulating RV-specific Th1 cells is limited to those infected patients who develop serum neutralizing antibodies, whereas this feature is lacking in those who are infected but fail to mount an antibody response. Nonetheless, there is also evidence of a pathogenic role for virus-specific Th1 cells in patients with asthma who are at risk of adverse sequelae, based on enhanced and persistent responses. We posit that a similar scenario underlies the “cytokine storm” and rapid decline in patients with severe COVID-19 and those who are at risk, thereby reflecting the double-edged sword of Th1 cells in anti-viral immunity. The technological tools and analytical pipelines developed to study cross-strain immunity to RV infections, coupled with access to COVID-19 patients and those at risk, allow us to pivot quickly to analyze T cell responses to SARS-CoV-2. Powerful single-cell analytical tools for interrogating large cell numbers will be used to test the theory that cross-reactive T cells respond rapidly to SARS-CoV-2, and their numbers and functional attributes determine disease status in healthy individuals and at-risk patients. Based on our expertise, we are uniquely poised to map CD4+ T cell epitopes across the SARS-CoV-2 proteome. These data will be used to generate MHCII/peptide tetramers to detect and phenotype cross-reactive SARS-CoV-2-specific memory CD4+ T cells that pre-exist in uninfected adults and persist in recovered COVID-19 patients. This will establish proof-of- concept for priming of T cells for rapid response by previous exposures to related coronavirus strains (Aim 1). Next, novel computational tools and tetramers will be used to identify hallmarks of overactive virus-specific T cells in hospitalized COVID-19 patients in the acute phase, and to assess immune paralysis and antibody deficiencies in those who develop respiratory failure (Aim 2). Finally, we will confirm in vivo expansion of virus- specific pathogenic Th1 cells in uninfected asthmatics with severe disease, and boosting of their function by pro-inflammatory cues present in the lower airways (Aim 3). Study outcomes will yield new insight into T cell mechanisms of viral pathogenesis, and aid in vaccine design and monitoring for COVID-19.

概括 了解对 SARS-CoV-2 的适应性反应对于阻止 SARS-CoV-2 造成的破坏至关重要 COVID-19 大流行，通过确定新的药物靶点并为疫苗的合理设计提供信息。常见的 冠状病毒和人鼻病毒 (RV) 都会引起普通感冒，并且每种病毒都存在多种毒株 具有不同程度的序列同一性。所有人类，尤其是成年人，都具有抗原经历 免疫细胞凭借频繁的病毒感染。我们在人类中使用 RV 进行实验性感染的工作 对这种相对良性但麻烦的病毒的适应性免疫提供了前所未有的见解。 开创性的发现包括交叉反应记忆 T 辅助细胞 1 (Th1) 快速动员的关键作用 细胞和 T-bet+ B 细胞控制 RV 感染。 Th1 细胞通过帮助病毒发挥作用，对于抗病毒反应至关重要 通过分泌 IFN-γ 进行清除，并帮助 B 细胞产生中和抗体。 值得注意的是，循环 RV 特异性 Th1 细胞的扩增仅限于那些出现血清 中和抗体，而那些被感染但未能产生抗体的人则缺乏此功能 回复。尽管如此，也有证据表明病毒特异性 Th1 细胞在患有以下疾病的患者中具有致病作用： 由于反应增强且持续，因此面临不良后遗症风险的哮喘患者。我们假设一个 类似的情况是“细胞因子风暴”的基础，重症 COVID-19 患者和重症患者的数量迅速下降。 Th1细胞在抗病毒免疫中是一把双刃剑。技术方面 开发工具和分析管道来研究对 RV 感染的交叉菌株免疫，并获得 COVID-19 患者和处于危险中的患者使我们能够快速分析 T 细胞对 SARS-CoV-2 的反应。 用于询问大量细胞的强大单细胞分析工具将用于测试以下理论： 交叉反应性 T 细胞对 SARS-CoV-2 做出快速反应，其数量和功能属性决定了 健康个体和高危患者的疾病状况。基于我们的专业知识，我们有独特的能力 绘制 SARS-CoV-2 蛋白质组中 CD4+ T 细胞表位的图谱。这些数据将用于生成 MHCII/肽四聚体用于检测交叉反应 SARS-CoV-2 特异性记忆 CD4+ T 细胞并进行表型分析 先前存在于未感染的成人中，并持续存在于康复的 COVID-19 患者中。这将建立证明- 通过先前接触相关冠状病毒株来启动 T 细胞快速反应的概念（目标 1）。 接下来，新的计算工具和四聚体将用于识别过度活跃的病毒特异性 T 的标志 住院的 COVID-19 患者急性期细胞，并评估免疫麻痹和抗体 呼吸衰竭患者的缺陷（目标 2）。最后，我们将确认病毒的体内扩增—— 未感染的患有严重疾病的哮喘患者中的特定致病性 Th1 细胞，并通过以下方法增强其功能 下呼吸道中存在促炎信号（目标 3）。研究结果将为 T 细胞带来新的见解 病毒发病机制，并帮助设计和监测 COVID-19。