Systems Immunogenetics of Influenza Virus Infection in the Collaborative Cross

摘要：甲型流感病毒(IAV)等呼吸道病毒在我国造成高发病率和高死亡率。 人类人口。宿主免疫反应在感染过程中既可以起到保护性作用，也可以起到病理作用。 因此，对调控网络和信号通路的了解决定了信号的大小和 个体抗病毒免疫反应的质量对人类健康具有重要影响，因为这些 基因/通路可以作为治疗的靶点来控制病毒复制，治疗异常免疫。 反应，或者它们可能是提高疫苗安全性和有效性的目标，以应对广泛的 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 需要在人类身上看到的遗传和表型多样性来机械地剖析免疫的遗传学 变种。为了满足这一需求，我们使用了协作杂交(CC)，这是一种高度多样化的小鼠基因 参考群体，以确定和表征调节基线和IAV-1的多态宿主基因 诱导先天免疫和获得性免疫。作为这项努力的一部分，我们量化了病毒诱导的 45天的先天和获得性免疫反应和疾病(2、4、7、10、15、28天和 在110个CC Rix系(CC重组自交系与CC重组自交系 (Ri)模拟杂合子人类种群的品系)。此资源在与其他资源相结合时 互补系统遗传学工具，如多样性远缘杂交(DO)群体和CRISPR介导的 基因组编辑，比较宿主对正在研究的其他病原体的反应的数据集 U19的背景，以及IAV感染者基因表达变化和遗传变异的分析 患者，使我们有机会：1)识别与IAV免疫反应相关的多态基因 变异，并测试它们对抗病毒反应或病毒诱导的疾病过程的其他方面的影响，2) 测试这些基因如何影响对其他病毒病原体的反应，或在过敏/自身免疫期间的功能，以及 3)在人类感染的背景下测试这些基因的影响，以确定诊断、预防 以及对人类的治疗干预。

Abstract: Respiratory viruses, such as influenza A virus (IAV) cause high levels of morbidity and mortality in human populations. Host immune responses can play either protective or a pathologic role during infection. 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 control viral replication, to treat aberrant immune responses, or they 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 are needed to mechanistically dissect the genetics of immune variation. To address this need, we have used the Collaborative Cross (CC), a highly diverse mouse genetic reference population, to identify and characterize polymorphic host genes that regulate baseline and IAV- induced innate and adaptive immunity. As part of this effort, we have quantified variation in virus-induced innate and adaptive immune responses and disease over a 45 day time-course (Days 2, 4, 7, 10, 15, 28, and 45 post infection) in a panel of 110 CC RIX lines (reproducible F1 crosses between CC recombinant inbred (RI) lines that model heterozygous human populations). This resource, when combined with other complementary Systems Genetics tools, such as the Diversity Outbred (DO) population and CRISPR-mediated genome editing, data sets comparing the host response to other pathogens that are being studied in the context of this U19, and the analysis of gene expression changes and genetic variations in IAV infected human patients, gives us the opportunity to: 1) identify polymorphic genes associated with IAV immune response variation, and test their impact on other aspects of the antiviral response or virus-induced disease process, 2) test how these genes impact responses to other viral pathogens, or function during allergy/auto-immunity, and 3) test the impact of these genes in the context of human infections to identify targets for diagnosis, prevention and therapeutic interventions in humans.