MHC Variation in Host Response to SARS-CoV2 and COVID-19 Outcomes

宿主对 SARS-CoV2 和 COVID-19 结果反应的 MHC 变化

基本信息

批准号：
10297642
负责人：
JILL Allison HOLLENBACH
金额：
$ 80.95万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-13 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10297642
关键词：
2019-nCoV 6p21 Alleles Antibodies Antigen Presentation Antigenic Variation Autoimmunity B-Lymphocytes Big Data Bioinformatics Biology Blood Bone Marrow CD4 Positive T Lymphocytes COVID-19 COVID-19 patient Cells Chromosomes Clinical Clinical Data Communicable Diseases Coupled Coupling Custom Data Data Set Disease Disease Outcome Drug Hypersensitivity Elements Epidemiology Epitopes Fostering Foundations Genes Genetic Genomic Segment Genomics Genotype Goals HLA Antigens Health Health system Histocompatibility Antigens Class I Histocompatibility Antigens Class II Human Human Genome Immune Immune response Immune system Immunity Immunogenetics Immunologics Immunology Immunotherapy Infection Investigation Laboratories Link Lung Major Histocompatibility Complex Malignant Neoplasms Maps Marrow Medical Medical Genetics Methods Molecular Molecular Biology Nature Nucleoproteins Outcome Patients Peptides Phenotype Play Population Genetics Proteins Proteomics Registries Resolution Resources Risk Factors Role SARS-CoV-2 antigen SARS-CoV-2 infection Sample Size Sampling Specificity Symptoms T cell response T-Lymphocyte T-Lymphocyte Epitopes Technology Testing Untranslated RNA Validation Variant Virus Diseases antigen binding base citizen science cohort cytokine data resource deep sequencing disorder risk donor stem cell immune activation innovation insight longitudinal analysis mobile computing next generation sequencing novel pathogen programs repository response smartphone Application vaccine development volunteer

项目摘要

SUMMARY Located within the human Major Histocompatibility Complex (MHC) chromosome 6p21, the Human Leukocyte Antigen (HLA) region is the most medically important region of the human genome. Variation in the HLA region has been associated with over 150 diseases and conditions, including infectious disease, cancers, and major drug-hypersensitivities. While little is known at this point about the impact of host genetic factors in COVID-19, the epidemiology to-date reveals wide variation in disease course among confirmed cases of infection that does not appear to be fully explained by known risk factors. Because of its pivotal role in the immune response understanding the role of HLA variation promises to provide important insights relevant to understanding the immunopathogenesis of COVID-19, while informing vaccine development and potential immunotherapies. In Specific Aim 1, we will exploit an existing data resource, partnering with the National Marrow Donor Program and DKMS registries to collect data on COVID-19 symptoms, testing and outcomes using a novel, validated smartphone app in a very large sample (N=300,000-500,000) of volunteer bone marrow donors with pre-existing HLA genotyping data, allowing an extraordinarily well-powered examination of the role of these genes in disease. In Specific Aim 2, we will employ a novel, validated method for next-generation sequencing of the extended MHC (~5Mb), including all classical and non-classical HLA loci, as well as over 150 additional immune system loci, in large and diverse cohorts of COVID-19 patients (N=2000), as well patient cohorts with longitudinal clinical data and extensive immunoprofiling (N=300). Finally, in Specific Aim 3 we will contextualize these association studies through examination of the role of HLA presentation of SARS-CoV-2 antigens. In summary, we will leverage large and diverse patient cohorts alongside cutting edge technology and molecular biology to reveal the role of these important immune loci in COVID-19.

概括人类白细胞位于人类主要组织相容性复合体 (MHC) 染色体 6p21 内抗原（HLA）区域是人类基因组中医学上最重要的区域。 HLA 区域的变异与 150 多种疾病和病症有关，包括传染病、癌症和重大疾病药物过敏。虽然目前对于宿主遗传因素对 COVID-19 的影响知之甚少，迄今为止的流行病学显示，确诊感染病例的病程存在很大差异，已知的风险因素似乎无法完全解释。由于其在免疫反应中的关键作用了解 HLA 变异的作用有望为理解 HLA 变异提供重要的见解。 COVID-19 的免疫发病机制，同时为疫苗开发和潜在的免疫疗法提供信息。在具体目标 1，我们将与国家骨髓捐赠计划合作，利用现有的数据资源和 DKMS 注册中心，使用经过验证的新型方法收集有关 COVID-19 症状、检测和结果的数据智能手机应用程序在一个非常大的样本（N = 300,000-500,000）的志愿者骨髓捐赠者中进行 HLA 基因分型数据，可以对这些基因在疾病中的作用进行非常有力的检查。在具体目标 2 中，我们将采用一种新颖的、经过验证的方法对扩展的 MHC 进行下一代测序 (~5Mb)，包括所有经典和非经典 HLA 基因座，以及超过 150 个额外的免疫系统基因座，大量且多样化的 COVID-19 患者队列 (N=2000)，以及具有纵向临床数据的患者队列和广泛的免疫分析（N=300）。最后，在具体目标 3 中，我们将结合这些关联研究的背景通过检查 SARS-CoV-2 抗原的 HLA 呈递的作用。总而言之，我们将利用庞大且多样化的患者群体以及尖端技术和分子生物学揭示了 COVID-19 中的这些重要免疫位点。