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COVID-19: Characterizing trained immune responses to COVID-19

COVID-19：描述针对 COVID-19 的训练有素的免疫反应

基本信息

批准号：
10339451
负责人：
JONATHAN P MOORMAN
金额：
--
依托单位：
JAMES H QUILLEN VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10339451
关键词：
2019-nCoV Acute Adaptive Immune System Antigens B-Lymphocytes Biological Assay C Type Lectin Receptors COVID-19 COVID-19 pathogenesis COVID-19 patient Cell physiology Cells China Clinical Complex Consensus Coronavirus Data Development Elderly Epigenetic Process Exhibits Exposure to Gene Expression Regulation Healthcare Systems Human Immune Immune response Immune system Immunity Immunologic Memory Infection Infectious Agent Innate Immune Response Lead Link Lung Lung diseases Mediating Metabolic Metabolism Middle East Respiratory Syndrome Coronavirus Molecular Natural Immunity Natural Killer Cells Nucleic Acids Pathogenesis Patients Pattern Pattern recognition receptor Phenotype Play Population Process Recovery Resistance Role SARS coronavirus SARS-CoV-2 antigen SARS-CoV-2 exposure SARS-CoV-2 immunity SARS-CoV-2 infection SARS-CoV-2 pathogenesis Secondary to Signal Transduction T-Lymphocyte Training Vaccine Design Viral Viral Antigens Viral Proteins Virus Virus Diseases Vulnerable Populations adaptive immune response adaptive immunity betacoronavirus cohort coronavirus disease cross reactivity cytokine human coronavirus macrophage monocyte novel pandemic disease pathogen rational design receptor respiratory virus response translational study

项目摘要

In late 2019, a novel human betacoronavirus emerged in Wuhan, China and subsequently led to pandemic spread. Designated Severe Acute Respiratory Virus 2 (SARS CoV-2), this virus has spawned a coronaviral infection (COVID-19) that has threatened world populations and overwhelmed healthcare systems globally. Host immune responses during COVID-19 clearly play a significant role in viral clearance as well as pulmonary progression, but these responses are yet to be characterized. Most notably, the innate immune responses required for viral clearance and resistance to repeated infections are not yet known. Recent studies also suggest that these innate immune responses can also form immunologic memory (“trained immunity”) that occurs independently of B and T cells and results from epigenetic reprogramming of monocytes, macrophage and NK cell functions that alters their intracellular signaling and cellular metabolism patterns. This reprogramming allows them to acquire enhanced capability to respond to secondary stimulation by related or unrelated infectious agents. Because data from related coronaviruses suggest that innate immune responses are fundamentally important to pathogenesis, we hypothesize that NK/monocyte responses to viral proteins are necessary to maximize host immune responses. In this proposal, we will comprehensively investigate the importance of innate immune cells in the development of anamnestic adaptive responses to SARS CoV-2 antigen, and the role of NK and monocytes/macrophages in trained innate immune responses to viral antigen, from a clinically characterized cohort of COVID-19 patients following recovery. In aim 1, we will determine the importance of innate immune responses in responding to repeat exposure to viral antigens following COVID-19 recovery by 1) assessing the necessity of innate immune cells in generating anamnestic adaptive cellular responses to SARS CoV-2, and 2) characterizing the cross-reactivity of betacoronaviral antigens in inducing NK/monocyte responses including phenotypic changes, activation, proliferation, and cytokine expression, in COVID-recovered subjects. In aim 2, we identify innate trained immune responses to SARS CoV-2 antigens following COVID-19 recovery by examining if either NK cells or monocytes/macrophages from COVID-19 recovered subjects exhibit innate immune memory to SARS CoV-2 as assayed by functional, metabolic, and epigenetic changes These novel translational studies will produce key, relevant data on host immunity to COVID-19 infection, informing vaccine design and enhancing our understanding of innate immune memory and the correlates of protective immunity.

2019年底，中国武汉出现了一种新型人类β冠状病毒，随后导致流行病蔓延。指定的严重急性呼吸道病毒2（SARS CoV-2），这种病毒已经产生了一个冠状病毒感染（COVID-19）已威胁到世界人口并使医疗保健不堪重负全球系统。COVID-19期间的宿主免疫反应显然在病毒感染中起着重要作用清除以及肺部进展，但这些反应尚待表征。最值得注意的是，清除病毒和抵抗反复感染所需的先天免疫应答，还不知道。最近的研究还表明，这些先天免疫反应也可以形成免疫记忆（“训练的免疫”），不依赖于B和T细胞发生，由单核细胞、巨噬细胞和NK细胞功能的表观遗传重编程改变了它们的细胞内信号传导和细胞代谢模式。这种重新编程使它们能够获得增强的对相关或不相关的感染因子的继发性刺激作出反应的能力。因为数据来自相关的冠状病毒表明先天免疫应答对发病机理至关重要，我们假设NK/单核细胞对病毒蛋白的反应是最大化宿主免疫的必要条件，应答在这项提案中，我们将全面研究先天免疫细胞在免疫系统中的重要性。对SARS CoV-2抗原的记忆适应性反应的发展，以及NK和单核细胞/巨噬细胞对病毒抗原的先天性免疫应答，来自临床恢复后的COVID-19患者的特征队列。在目标1中，我们将确定在COVID-19后重复暴露于病毒抗原的先天免疫反应通过1）评估先天免疫细胞在产生记忆适应性细胞免疫应答中的必要性，对SARS CoV-2的反应，和2）表征β冠状病毒抗原在诱导NK/单核细胞应答，包括表型变化、活化、增殖和细胞因子在COVID康复受试者中的表达。在目标2中，我们确定了对SARS的先天训练免疫应答 COVID-19恢复后的CoV-2抗原，通过检查NK细胞或单核细胞/巨噬细胞从COVID-19康复受试者表现出对SARS CoV-2的先天免疫记忆，这些新的翻译研究将产生关键的，相关的，关于宿主对COVID-19感染的免疫力的数据，为疫苗设计提供信息并增强我们的理解先天免疫记忆和保护性免疫的相关性。