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鼠标数据 并通过研究人类对结核病的卡介苗反应和易感性。初级阶段 目的是了解人类基因变异如何调节巨噬细胞对结核分枝杆菌感染的免疫反应， 活体T细胞对卡介苗接种的反应，结核分枝杆菌菌株类型与肺结核病的关系，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，我们利用基因研究发现了 调节巨噬细胞的常见人类Toll样受体(TLR)途径的多态性特征 树突状细胞分泌细胞因子等宿主防御途径。类似于基因缺失研究 小鼠，这些天然的多态使我们能够检查人类先天免疫基因和 评估它们在体外细胞功能、体内疫苗T细胞反应和临床结核病易感性中的作用 疾病。在核心B中，我们将研究项目1至3中确定的候选结核病易感基因。我们将 确定候选小鼠结核病易感基因是否包含具有功能和 控制结核分枝杆菌在感染的巨噬细胞中的复制。使用候选基因病例对照研究，确定 小鼠结核病易感基因是否与成人肺结核易感性有关 越南，南非卡介苗诱导的T细胞反应，和/或南非的儿科结核病。我们 假设候选结核病易感基因中选定的DNA变异与结核病有关 和卡介苗应答，控制基因表达和/或蛋白功能，并介导有效的抗 微生物巨噬细胞对结核分枝杆菌感染的反应。由流行病学家、遗传学家组成的多学科团队， 与免疫学家合作超过10年，我们建议将遗传学和细胞学结合起来 分析结核分枝杆菌感染人巨噬细胞和临床队列以揭示其发病机制 常见的人类基因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.