Systems Immunogenetics of Biodefense and Emerging Pathogens in the Collaborative Cross

生物防御和新兴病原体协同交叉的系统免疫遗传学

• 批准号: 10265701
• 负责人: Ralph S Baric
• 金额: $ 9.12万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265701
• 关键词: Affect; Antiviral Agents; Autoimmunity; Automobile Driving; Biological Models; Clustered Regularly Interspaced Short Palindromic Repeats; Data Set; Databases; Diagnosis; Disease; Environmental Risk Factor; Ethics; Gene Combinations; Genes; Genetic; Genetic Variation; Health; Human; Hypersensitivity; Immune; Immune System Diseases; Immune response; Immunity; Immunogenetics; Inbreeding; Individual; Infection; Inflammation; Influenza A virus; Maps; Mediating; Modeling; Morbidity - disease rate; Mus; Natural Immunity; Pathogenesis; Pathologic; Pathway interactions; Phenotype; Play; Population; Quantitative Genetics; Quantitative Trait Loci; Recombinants; Reproducibility; Research; Research Design; Role; SARS coronavirus; Sampling; Shapes; Signal Pathway; System; Testing; Therapeutic Intervention; Time; Variant; Viral Pathogenesis; Virus; Virus Diseases; West Nile virus; adaptive immunity; biodefense; cohort; emerging pathogen; genome editing; genomic locus; mortality; mouse genetics; pathogenic virus; preventive intervention; programs; respiratory virus; response; therapeutic target; tool; vaccine efficacy; vaccine safety; Affect; Antiviral Agents; Autoimmunity; Automobile Driving; Biological Models; Clustered Regularly Interspaced Short Palindromic Repeats; Data Set; Databases; Diagnosis; Disease; Environmental Risk Factor; Ethics; Gene Combinations; Genes; Genetic; Genetic Variation; Health; Human; Hypersensitivity; Immune; Immune System Diseases; Immune response; Immunity; Immunogenetics; Inbreeding; Individual; Infection; Inflammation; Influenza A virus; Maps; Mediating; Modeling; Morbidity - disease rate; Mus; Natural Immunity; Pathogenesis; Pathologic; Pathway interactions; Phenotype; Play; Population; Quantitative Genetics; Quantitative Trait Loci; Recombinants; Reproducibility; Research; Research Design; Role; SARS coronavirus; Sampling; Shapes; Signal Pathway; System; Testing; Therapeutic Intervention; Time; Variant; Viral Pathogenesis; Virus; Virus Diseases; West Nile virus; adaptive immunity; biodefense; cohort; emerging pathogen; genome editing; genomic locus; mortality; mouse genetics; pathogenic virus; preventive intervention; programs; respiratory virus; response; therapeutic target; tool; vaccine efficacy; vaccine safety

Abstract: Emerging viruses, such as SARS-CoV, influenza A virus (IAV), and West Nile virus (WNV) cause high levels of morbidity and mortality in human populations. Host immune responses can play either protective or a pathologic role during viral infections. Therefore, understanding of the regulatory networks and signaling pathways that determine the magnitude and quality of an individual's antiviral immune response has important implications for human health, since these genes/pathways could be therapeutically targeted to treat virus- induced disease, or may represent targets for enhancing the safety and efficacy of vaccines against a wide range of viral pathogens. Polymorphic host genes and regulatory networks have a major impact on immune response variation in human populations. However, confounding environmental factors and/or ethical concerns limit the types of studies that can be conducted in humans. Therefore, genetically tractable model systems that capture the range of genetic and phenotypic diversity seen in humans, such as the Collaborative Cross (CC) are needed to mechanistically dissect the genetics of immune variation. Our research team has quantified variation in baseline, as well as SARS-CoV, IAV, and WNV-induced immune responses in a panel of 110 CC RIX lines (reproducible F1 crosses between CC recombinant inbred (RI) lines that model heterozygous human populations). To our knowledge, this represents to most comprehensive analysis of immune response variation ever conducted in a genetic reference population, and in ongoing QTL mapping studies, we have identified 100+ quantitative trait loci (QTL) associated with variation in virus-induced innate and adaptive immunity, inflammation and disease. Our program, which includes expertise in viral pathogenesis, innate and adaptive immunity, and quantitative genetics will use this unprecedented data base to: 1) identify and characterize polymorphic host genes that drive variation in virus-induced disease, 2) test how interactions between different polymorphic genes/loci shape the host immune response, 3) test how these genes impact responses to other viral pathogens, or function during allergy/auto-immunity, and 4) test the impact of these genes in the context of human infections to identify targets for diagnosis, prevention and therapeutic interventions in humans. These studies will significantly enhance our understanding of how host genetic variation shapes virus-induced immunity and/or disease.

摘要：新兴病毒，例如SARS-COV，流感病毒（IAV）和西尼罗河病毒（WNV）引起 人口中高水平的发病率和死亡率。宿主免疫反应可以发挥保护作用 或病毒感染期间的病理作用。因此，了解监管网络和信号 确定个体抗病毒免疫反应的大小和质量的途径很重要 对人类健康的影响，因为这些基因/途径可以治疗以治疗病毒 - 诱发疾病，或可能代表增强疫苗对宽阔的安全性和功效的靶标 病毒病原体范围。 多态性宿主基因和调节网络对人的免疫反应变化有重大影响 人群。但是，混淆环境因素和/或道德问题限制了研究类型 可以在人类中进行。因此，捕获的遗传操作模型系统 在人类中看到的遗传和表型多样性，例如协作交叉（CC） 机械地剖析免疫变异的遗传学。我们的研究团队已经量化了 基线以及SARS-COV，IAV和WNV诱导的免疫反应在110 cc Rix线的面板中 （可重现的F1在CC重组近交（RI）线之间的交叉，该线模拟了杂合的人 人口）。据我们所知，这代表了对免疫反应变化的最全面分析 曾经在遗传参考人群中进行，在正在进行的QTL映射研究中，我们已经确定了 与病毒诱导的先天和适应性免疫变化相关的100+定量性状基因座（QTL）， 炎症和疾病。我们的计划包括病毒发病机理，先天和适应性方面的专业知识 免疫力和定量遗传学将使用此前所未有的数据库来：1）识别和表征 驱动病毒诱发疾病变化的多态性宿主基因，2）测试不同的相互作用如何之间的相互作用 多态基因/基因座塑造宿主免疫反应，3）测试这些基因如何影响对其他的反应 病毒病原体或在过敏/自身免疫性期间的功能，以及4）测试这些基因在上下文中的影响 人类感染以识别人类诊断，预防和治疗干预措施的靶标。 这些研究将显着增强我们对宿主遗传变异如何塑造病毒诱导的理解 免疫和/或疾病。