Systems Immunogenetics of Biodefense and Emerging Pathogens in the Collaborative Cross

摘要：新出现的病毒如SARS冠状病毒、甲型流感病毒和西尼罗河病毒引起 人类人口的高发病率和死亡率。宿主免疫反应可以起到保护作用 或病毒感染过程中的病理作用。因此，了解调控网络和信令 决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/途径可能被用于治疗病毒- 诱发疾病，或可能是加强疫苗安全性和有效性的目标，以预防广泛的 病毒病原体的范围。 宿主基因和调控网络的多态对人类免疫反应的变异有重要影响 人口。然而，混淆的环境因素和/或伦理问题限制了研究的类型。 这可以在人类身上进行。因此，基因上易处理的模型系统捕捉到了 在人类中看到的遗传和表型多样性，如合作杂交(CC)是需要的 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在110个CC Rix系中诱导的免疫反应 (CC重组近交系(RI)之间可复制的F1杂交，模拟杂合子人类 种群)。据我们所知，这代表了对免疫反应变异的最全面的分析 以及正在进行的QTL定位研究中，我们已经确定 与病毒诱导的先天性免疫和获得性免疫的变异有关的100+数量性状基因座(QTL)， 炎症和疾病。我们的计划，包括病毒发病机制、先天和适应性方面的专业知识 免疫力和数量遗传学将利用这一史无前例的数据库：1)识别和表征 在病毒引起的疾病中驱动变异的多态宿主基因，2)测试不同宿主基因之间的相互作用 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 病毒病原体，或在过敏/自身免疫过程中的功能，以及4)在上下文中测试这些基因的影响 以确定人类感染的诊断、预防和治疗干预的目标。 这些研究将大大增强我们对宿主基因变异如何影响病毒诱导的理解 免疫力和/或疾病。

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.