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.

总结 了解对SARS-CoV-2的适应性反应对于阻止SARS造成的破坏至关重要。 通过确定新的药物靶点并为疫苗的合理设计提供信息，应对COVID-19大流行。共同 冠状病毒和人鼻病毒（RV）都能引起普通感冒，每种病毒都有多种毒株， 具有不同程度的序列同一性。所有的人，特别是成年人，都有抗原经历的 免疫细胞由于频繁的病毒感染。我们的工作是在人体内进行RV的实验性感染， 提供了对这种相对良性但麻烦的病毒的适应性免疫的前所未有的见解。 精液研究结果包括交叉反应性记忆辅助性T细胞1（Th 1）的快速动员的关键作用 细胞和T-bet+ B细胞在控制RV感染中的作用。Th 1细胞通过协助病毒介导的免疫应答而对抗病毒应答至关重要。 通过分泌IFN-γ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Th 1细胞的扩增仅限于那些产生血清抗体的感染患者。 中和抗体，而这一特点是缺乏那些谁感染，但未能安装抗体 反应尽管如此，也有证据表明，病毒特异性Th 1细胞在慢性乙型肝炎患者中具有致病作用。 哮喘患者有不良后遗症的风险，基于增强和持续的反应。我们假设 类似的情况是“细胞因子风暴”的基础，严重COVID-19患者和那些 这反映了Th 1细胞在抗病毒免疫中的双刃剑作用。技术 开发工具和分析管道，以研究RV感染的交叉菌株免疫力， COVID-19患者和那些处于风险中的人，使我们能够快速转向分析SARS-CoV-2的T细胞反应。 强大的单细胞分析工具，询问大细胞数量将被用来测试的理论， 交叉反应性T细胞对SARS-CoV-2反应迅速，它们的数量和功能属性决定了 健康个体和高危患者的疾病状态。基于我们的专业知识，我们有独特的优势， 绘制SARS-CoV-2蛋白质组中的CD 4 + T细胞表位。这些数据将用于生成 MHCII/肽四聚体检测和表型交叉反应SARS-CoV-2特异性记忆CD 4 + T细胞 在未感染的成年人中预先存在，并在康复的COVID-19患者中持续存在。这将证明- 通过先前暴露于相关冠状病毒株引发T细胞快速反应的概念（目的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细胞的标志。 在急性期住院的COVID-19患者的细胞，并评估免疫麻痹和抗体 呼吸衰竭的患者（目标2）。最后，我们将确认病毒在体内的扩增- 未感染的重症哮喘患者中特异性致病性Th 1细胞， 下气道中存在的促炎线索（Aim 3）。研究结果将对T细胞产生新的见解 病毒发病机制，并有助于疫苗设计和监测COVID-19。