Natural Killer cells and the Immunogenetics of COVID-19

自然杀伤细胞和 COVID-19 的免疫遗传学

• 批准号: 10297139
• 负责人: Paul John Norman
• 金额: $ 74.28万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10297139
• 关键词: 2019-nCoV; A549; Address; Affect; Age; Algorithms; Alleles; Antibodies; Biological Assay; Brazil; COVID-19; COVID-19 pandemic; COVID-19 patient; COVID-19 treatment; Cell physiology; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Complement; Country; Data; Data Set; Detection; Development; Diagnosis; Disease; Effector Cell; Ensure; Epidemic; Epidemiology; Epithelial; Epitopes; Ethnic Origin; Ethnic group; Flow Cytometry; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Genotype; Geography; Goals; HIV-1; HLA Antigens; Herpesviridae; Histocompatibility Antigens Class I; Human; Immune; Immune response; Immunity; Immunogenetics; Immunoglobulins; Individual; Infection; Infection Control; Influenza; Italy; Killer Cells; Laboratories; Lead; Left; Ligands; Lung; Measures; Mediating; Methods; Natural Immunity; Natural Killer Cells; Nature; Outcome; Patients; Peptides; Phenotype; Population; Population Group; Predisposition; Prevention; Preventive measure; Proteins; Race; Receptor Gene; Recording of previous events; Research Personnel; Resistance; Resolution; Risk; Risk Factors; Role; SARS-CoV-2 infection; SARS-CoV-2 spike protein; Sampling; Severe Acute Respiratory Syndrome; Severity of illness; Spain; Specificity; Structure of parenchyma of lung; Surface; Sweden; Symptoms; Target Populations; Testing; Therapeutic; Time; Tissues; Vaccine Design; Variant; Viral; Virus; Virus Diseases; adaptive immune response; adaptive immunity; antibody-dependent cell cytotoxicity; biobank; cell killing; cohort; cytokine; cytotoxicity; experimental study; genetic analysis; humanized monoclonal antibodies; imprint; multi-ethnic; pandemic disease; pathogen; personalized medicine; prevent; racial and ethnic; receptor; recruit; response; severe COVID-19; therapeutic target; vaccine evaluation

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.

概括 为了确保成功、持续地应对 COVID-19 危机，当务之急是 人类自然免疫中相当大的基因型和表型变异的功能意义是 明白了。自然杀伤 (NK) 细胞在控制先天性和适应性免疫反应中发挥着重要作用 病毒感染，包括疱疹病毒、HIV-1、流感和 SARS。 NK 细胞的重要组成部分 抵抗病原体入侵的前线防御，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，由杀伤细胞的相互作用调节 免疫球蛋白样受体 (KIR) 与组织细胞上表达的 I 类人类白细胞抗原 (HLA)。 在个体之间，可行的受体和配体对的数量和性质存在巨大差异 在个体中，存在多种 NK 细胞亚群，它们的受体不同。之前的研究 流行病的研究已经确定了这种多样性与易感性、抵抗力或 控制感染。 可能反映了整个人类历史上对多重、多样化和地理离散的接触 病原体的 HLA 和 KIR 基因在个体和人群中差异很大。这些 遗传变异直接影响 NK 细胞功能和对感染的反应。同种异型依赖性 KIR 与 HLA 的相互作用通知、调节和多样化 NK 细胞的识别和消除作用 病毒感染的组织细胞。因此，要考虑到人类群体中这种差异的全部程度 对于理解、诊断和治疗 SARS-CoV-2 感染以及开发和测试至关重要 疫苗。 我们将研究的首要假设是 HLA 和 KIR 的遗传变异可以决定 SARS-CoV-2 感染后的免疫过程，导致某些人出现严重的 COVID-19。第一个 我们研究的目的是对 11,500 名 SARS-CoV-2 感染患者组成的大型多种族队列进行检查，以确定 HLA 和 KIR 遗传多样性与疾病严重程度的关系。这些队列是从 受疫情影响最严重的国家包括巴西、意大利、西班牙、英国和美国。 NK 细胞识别 通过失去抑制性受体的配体或获得激活受体的配体来感染细胞。许多 已知病毒会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，以及其如何发挥作用 所有已知的 HLA 和 KIR 同种异型相互作用都有所不同。 NK 细胞可以被以下抗体激活： 与受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，最终目标将检查抗体依赖性消除的作用 SARS-CoV-2 感染细胞，以及 KIR 和 HLA 多态性对此反应的影响。验证我们的 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，我们的研究结果将 识别出最有可能罹患严重 COVID-19 的个体会产生直接后果， 开发通用和个性化治疗，并帮助疫苗设计。