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: 10686171
• 负责人: Paul John Norman
• 金额: $ 71.46万
• 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/10686171
• 关键词: 2019-nCoV; A549; Address; Affect; Age; Algorithms; Alleles; Antibodies; Binding; 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; Epithelium; Epitopes; Ethnic Origin; Ethnic Population; Flow Cytometry; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Genotype; Geography; Goals; HIV-1; HLA Antigens; Herpesviridae; Histocompatibility Antigens Class I; Hospitalization; Human; Immune Evasion; Immune response; Immunity; Immunogenetics; Immunoglobulins; Individual; Infection; Infection Control; Influenza; Innate Immune Response; Invaded; Italy; Killer Cells; Laboratories; 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 population; receptor; recruit; reduce symptoms; response; severe COVID-19; therapeutic target; vaccine evaluation; 2019-nCoV; A549; Address; Affect; Age; Algorithms; Alleles; Antibodies; Binding; 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; Epithelium; Epitopes; Ethnic Origin; Ethnic Population; Flow Cytometry; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Genotype; Geography; Goals; HIV-1; HLA Antigens; Herpesviridae; Histocompatibility Antigens Class I; Hospitalization; Human; Immune Evasion; Immune response; Immunity; Immunogenetics; Immunoglobulins; Individual; Infection; Infection Control; Influenza; Innate Immune Response; Invaded; Italy; Killer Cells; Laboratories; 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 population; receptor; recruit; reduce symptoms; 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 为了确保对19009危机的成功和持续的反应，必须 自然人免疫中相当大的基因型和表型变异的功能含义是 理解。天然杀手（NK）细胞在控制先天和适应性免疫反应中具有重要作用 病毒感染，包括疱疹病毒，HIV-1，流感和SARS。 NK细胞构成了重要的一部分 针对病原体入侵的前线防御，并在肺组织中大量存在。 NK细胞 效应子功能，包括细胞因子释放和细胞毒性，受杀伤细胞的相互作用调节 在组织细胞上表达的I类人白细胞抗原（HLA）的免疫球蛋白样受体（KIR）。 在个人之间，可行的受体和配体对的数量和性质都有巨大的多样性 在个体内部，有许多由其受体区别的NK细胞子集。先前的研究 流行病已经确定了这种多样性与敏感性，抵抗力或 控制感染。 可能反映在整个人类历史上的接触 病原体，HLA和KIR基因在个体和人群群体之间的变化很大。这些 遗传变异对NK细胞功能和对感染的反应有直接影响。异型依赖性 KIR与HLA信息的相互作用，调节和多样化NK细胞在识别和消除的作用中的作用 病毒感染的组织细胞。因此，考虑到整个人群的这种差异的全部范围是 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。 我们将研究的总体假设是，HLA和KIR的遗传变异可以确定 SARS-COV-2感染后的免疫力，导致某些个体严重的Covid-19。第一个 我们研究的目的将检查大量的多民族队列，包括11,500个SARS-COV-2感染患者，以确定 HLA和KIR遗传多样性与疾病严重程度的关联。同伙是从 国家受到大流行的影响，包括巴西，意大利，西班牙，英国和美国。 NK细胞识别 通过抑制受体的配体丧失或激活受体的配体获得的感染细胞。许多 已知病毒可以利用任何或全部这些机制来逃避免疫检测。第二个目标 检查SARS-COV-2衍生蛋白在逃避NK细胞驱动的免疫反应中的作用，以及如何 在所有已知的HLA和KIR同种型相互作用中各不相同。 NK细胞可以通过抗体激活 与受感染细胞表面的病毒段结合，我们已经表明，这种活性也取决于 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多态性对该反应的影响。验证我们的 我们的初步发现方法已经确定了一个潜在的治疗靶点。因此，我们的发现将 对于确定最有可能发展严重的共同证明的人，有直接的后果，因为 开发通用和个性化治疗，并帮助疫苗设计。