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

2019年末，一种新型人类β-冠状病毒在武汉出现，中国随后导致 大流行蔓延。这种病毒被称为严重急性呼吸道病毒2(SARS CoV-2)，已经产生了一种 冠状病毒感染(新冠肺炎)已威胁到世界人口并使医疗保健不堪重负 全球系统。新冠肺炎期间的宿主免疫反应显然在病毒感染中发挥了重要作用 清除以及肺部进展，但这些反应尚未确定。多数 值得注意的是，清除病毒和抵抗重复感染所需的先天免疫反应是 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(“训练性免疫”)，独立于B和T细胞而发生，其结果是 单核细胞、巨噬细胞和NK细胞功能的表观遗传重编程改变其细胞内 信号和细胞代谢模式。这种重新编程使他们能够获得增强的 对相关或非相关传染病病原体的二次刺激做出反应的能力。因为来自 相关冠状病毒提示，先天免疫反应在发病机制中具有根本性的重要作用， 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所必需的 回应。在这项建议中，我们将全面研究先天免疫细胞在 SARS冠状病毒-2抗原的记忆适应性反应的发展及NK和 单核/巨噬细胞对病毒抗原的先天免疫反应 新冠肺炎患者康复后的特征队列。在目标1中，我们将确定 新冠肺炎重复暴露病毒抗原对先天免疫反应的影响 通过1)评估先天免疫细胞在产生记忆适应性细胞中的必要性来恢复 对SARS CoV-2的应答，以及2)β冠状病毒抗原的交叉反应性 诱导NK/单核细胞反应，包括表型改变、激活、增殖和细胞因子 在COVID恢复的受试者中表达。在目标2中，我们确定了对SARS的先天训练免疫反应 新冠肺炎恢复后检测NK细胞或单核/巨噬细胞中的CoV-2抗原 新冠肺炎康复者对SARS CoV-2的天然免疫记忆 功能、代谢和表观遗传学变化这些新的翻译研究将产生关键的、相关的 关于宿主对新冠肺炎感染的免疫力的数据，为疫苗设计提供信息，增进我们的理解 与生俱来的免疫记忆和保护性免疫的相关性。

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.