Natural Killer cells and the Immunogenetics of COVID-19

总结 为确保成功和持续应对COVID-19危机， 在天然人类免疫中相当大的基因型和表型变异的功能含义是 明白自然杀伤（NK）细胞在控制先天性和适应性免疫应答中具有重要作用 病毒感染，包括疱疹病毒、HIV-1、流感和SARS。NK细胞构成了 是抵抗病原体入侵的第一线防御，大量存在于肺组织中。NK细胞 效应器功能，包括细胞因子释放和细胞毒性，通过杀伤细胞的相互作用来调节， 免疫球蛋白样受体（KIR）与组织细胞上表达的I类人白细胞抗原（HLA）。 在个体之间，有活力的受体和配体对的数量和性质存在巨大的差异 在个体内，有许多NK细胞亚群，它们的受体是不同的。以前的研究 流行病的研究已经确定了这种多样性与易感性、耐药性或 控制感染。 很可能反映了人类历史上受到多种、多样和地理上分散的 在病原体中，HLA和KIR基因在个体和人群中高度可变。这些 遗传变异对NK细胞功能和对感染的反应有直接影响。同种异型依赖性 KIR与HLA的相互作用通知、调节和多样化NK细胞在其识别和消除 病毒感染的组织细胞因此，考虑到整个人群中这种差异的程度， 对于理解、诊断和治疗SARS-CoV-2感染以及开发和测试 疫苗。 我们将研究的总体假设是，HLA和KIR的遗传变异可以决定 SARS-CoV-2感染后的免疫过程，导致某些个体出现严重的COVID-19。第一 本研究的目的是对11，500名SARS-CoV-2感染患者的大型多种族队列进行研究，以确定 HLA和KIR遗传多样性与疾病严重程度的关系。这些队列来自 受疫情影响最严重的国家，包括巴西、意大利、西班牙、英国及美国。NK细胞识别 通过抑制性受体配体的丢失或激活性受体配体的获得而感染细胞。许多 已知病毒利用任何或所有这些机制来逃避免疫检测。第二个目标将 研究SARS-CoV-2衍生蛋白在逃避NK细胞驱动的免疫反应中的作用，以及这是如何发生的。 在所有已知的HLA和KIR同种异型相互作用中存在差异。NK细胞可以被抗体激活， 与感染细胞表面的病毒片段结合，我们已经证明这种活性也依赖于 HLA和KIR多样性。因此，最终目的将研究抗体依赖性消除的作用， SARS-CoV-2感染的细胞，以及KIR和HLA多态性对这种反应的影响。验证我们 通过这种方法，我们的初步研究结果已经确定了一个潜在的治疗靶点。因此，我们的发现将 对识别最有可能患上严重COVID-19的个人具有直接影响， 开发通用和个性化治疗，并帮助疫苗设计。

Summary To ensure a successful and sustained response to the COVID-19 crisis it becomes imperative that the functional implications of the considerable genotypic and phenotypic variation in natural human immunity are understood. Natural killer (NK) cells have major roles in controlling the innate and adaptive immune response to viral infections, including herpesviruses, HIV-1, influenza, and SARS. NK cells comprise a significant part of the front-line defense against pathogen invasions and are present at large numbers in lung tissues. NK cell effector functions, including cytokine release and cytotoxicity, are modulated by interactions of killer cell immunoglobulin-like receptors (KIR) with class I human leukocyte antigens (HLA) expressed on tissue cells. Across individuals, there is enormous diversity in the number and nature of viable receptor and ligand pairs and within individuals, there is a multitude of NK cell subsets distinguished by their receptors. Previous studies of epidemic diseases have identified clear relationships between this diversity and susceptibility, resistance or control of infection. Likely reflecting exposure throughout human history to multiple, diverse and geographically discrete pathogens, the HLA and KIR genes are highly variable across individuals and population groups. These genetic variations have direct impact on NK cell functions and the response to infection. Allotype-dependent interactions of KIR with HLA inform, modulate and diversify NK cells in their role of identifying and eliminating virus-infected tissue cells. Consideration of the full extent of this variation across human populations is thus critical to understanding, diagnosing and treating SARS-CoV-2 infection, and for developing and testing vaccines. The overarching hypothesis that we will investigate is that genetic variation of HLA and KIR can determine the course of immunity following SARS-CoV-2 infection, leading to severe COVID-19 in some individuals. The first Aim of our study will examine a large multi-ethnic cohort of 11,500 SARS-CoV-2 infected patients, to determine the association of HLA and KIR genetic diversity with severity of disease. The cohorts are drawn from the countries hardest hit by the pandemic, including Brazil, Italy, Spain, UK and the USA. NK cells recognize infected cells through loss of ligands for inhibitory receptors or gain of ligands for activating receptors. Many viruses are known to exploit any or all of these mechanisms to evade immune detection. The second Aim will examine the role of SARS-CoV-2 derived proteins in evading NK cell driven immune responses, and how this varies across all known HLA and KIR allotype interactions. NK cells can be activated by antibodies that are bound to virus segments on the surface of infected cells, and we have shown this activity is also dependent on HLA and KIR diversity. The final Aim will therefore examine the role of antibody-dependent elimination of SARS-CoV-2 infected cells, and the impact of KIR and HLA polymorphism on this response. Validating our approach, our preliminary findings already identified one potential therapeutic target. Our findings will thus have immediate consequence for identifying individuals most at risk for developing severe COVID-19, for developing both universal and personalized treatment, and to aid in vaccine design.