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: 10477389
• 负责人: Paul John Norman
• 金额: $ 71.48万
• 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/10477389
• 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; Persons; 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; post SARS-CoV-2 infection; 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.

摘要 为了确保成功和持续地应对新冠肺炎危机，当务之急是 自然人类免疫中相当大的基因和表型变异的功能含义是 明白了。自然杀伤(NK)细胞在控制先天和获得性免疫反应中起着重要作用。 病毒感染，包括疱疹病毒、HIV-1、流感和SARS。NK细胞是人类免疫功能的重要组成部分。 是抵御病原体入侵的前线防御系统，大量存在于肺组织中。NK细胞 效应功能，包括细胞因子的释放和细胞毒性，是由杀伤细胞的相互作用调节的 免疫球蛋白样受体(KIR)与人类I类白细胞抗原(HLA)在组织细胞上表达。 在个体中，存活的受体和配体对的数量和性质存在巨大的多样性。 在个体内，有许多NK细胞亚群通过它们的受体来区分。以前的研究 已经确定了这种多样性与易感性、耐药性或 控制感染。 可能反映了人类历史上对多种、多样化和地理上离散的接触 病原体、人类白细胞抗原基因和KIR基因在不同个体和人群中具有很高的变异性。这些 遗传变异直接影响NK细胞的功能和对感染的反应。同种异型依赖 KIR与人类白细胞抗原相互作用在NK细胞识别和消除中的信息、调节和多样化作用 病毒感染的组织细胞。因此，对人类群体中这种差异的全面程度的考虑是 对了解、诊断和治疗SARS-CoV-2感染以及开发和检测至关重要 疫苗。 我们将调查的最重要的假设是，人类白细胞抗原和KIR的遗传变异可以决定 SARS-CoV-2感染后的免疫过程，导致一些人出现严重的新冠肺炎。第一 我们研究的目的将检查11,500名SARS-CoV-2感染患者的大型多民族队列，以确定 人类白细胞抗原和KIR基因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 通过失去抑制受体的配基或获得激活受体的配基而感染细胞。许多 众所周知，病毒利用任何或所有这些机制来逃避免疫检测。第二个目标是 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，以及这是如何实现的 在所有已知的人类白细胞抗原和KIR同种异型相互作用中都不同。NK细胞可被下列抗体激活 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 HL A和KIR的多样性。因此，最终目标将检验抗体依赖消除的作用。 SARS-CoV-2感染细胞，以及KIR和HLA基因多态性对这一反应的影响。验证我们的 我们的初步发现已经确定了一个潜在的治疗靶点。我们的发现将因此 对确定患严重新冠肺炎风险最高的个人有直接影响， 开发通用和个性化的治疗方法，并协助疫苗设计。