Human Genetics and Clinical Studies

摘要 这一核心将通过与每个项目的互动，促进在人类队列中验证小鼠数据 以及通过研究人BCG应答和对TB疾病的易感性的特征。主 目的是了解人类遗传变异如何调节巨噬细胞对结核分枝杆菌感染的免疫反应， 体内T细胞对BCG疫苗接种的反应，Mtb菌株类型与肺结核的相关性，以及总体 对结核病的临床易感性。在过去的10年里，在西雅图，我们利用遗传学研究发现， 表征调节巨噬细胞的常见人Toll样受体（TLR）途径多态性 以及树突细胞细胞因子分泌和其它宿主防御途径。与基因缺失研究相似， 这些Au naturel多态性使我们能够检查人类先天免疫基因的缺陷， 评估它们在离体细胞功能、体内疫苗T细胞应答和对TB的临床易感性中的作用 疾病在核心B中，我们将检查项目1至3中确定的候选结核病易感基因。我们将 确定候选小鼠TB易感性基因是否含有功能性的DNA变体， 控制感染巨噬细胞中MTb的复制。使用候选基因病例对照研究，确定 小鼠结核易感基因是否与成人肺结核病易感性相关， 越南、南非的BCG诱导的T细胞应答和/或南非的儿童结核病。我们 假设候选TB易感基因中的选定DNA变异与TB疾病相关 和BCG疫苗应答，控制基因表达和/或蛋白质功能，并介导有效的抗- 微生物巨噬细胞对Mtb感染的反应。与一个由流行病学家，遗传学家， 和免疫学家超过10年的合作，我们建议将遗传和细胞结合起来， 分析结核分枝杆菌感染的人类巨噬细胞和人类临床队列，以发现如何 常见的人类遗传变异调节卡介苗诱导的免疫反应和对结核病的易感性。

Abstract This core will facilitate the validation of mouse data in human cohorts through interactions with each project and by pursuing the characterization of human BCG responses and susceptibility to TB disease. The primary goal is to understand how human genetic variation regulates macrophage immune responses to Mtb infection, in vivo T-cell responses to BCG vaccination, Mtb strain type associations with pulmonary TB, and overall clinical susceptibility to TB. Over the past 10 years in Seattle, we used genetic studies to discover and characterize common human Toll-like Receptor (TLR) pathway polymorphisms which regulate macrophage and dendritic cell cytokine secretion and other host-defense pathways. Similar to gene deletion studies in mice, these au naturel polymorphisms enable us to examine deficiencies of human innate immunity genes and assess their role in ex vivo cellular function, in vivo vaccine T-cell responses, and clinical susceptibility to TB disease. In Core B, we will examine candidate TB susceptibility genes identified in Projects 1 to 3. We will determine whether candidate mouse TB susceptibility genes contain DNA variants which are functional and control replication of MTb in infected macrophages. Using a candidate gene case-control study, determine whether mouse TB susceptibility genes are associated with susceptibility to adult pulmonary TB disease in Vietnam, BCG-induced T-cell responses in South Africa, and/or pediatric TB disease in South Africa. We hypothesize that selected DNA variants in candidate TB susceptibility genes are associated with TB disease and BCG vaccine responses, control gene expression and/or protein function and mediate an effective anti- microbial macrophage response to Mtb infection. With a multidisciplinary team of epidemiologists, geneticists, and immunologists with over 10 years of collaborative work together, we propose to couple genetic and cellular analysis of Mtb-infected human macrophages and human clinical cohorts to discover the mechanisms of how common human genetic variation regulates BCG-induced immune responses and susceptibility to TB.