PROJECT 1: Identification of host and bacterial pathways that control tuberculosis pathogenesis in humans

项目1：确定控制结核病的宿主和细菌途径 人类的致病机制 摘要 哺乳动物先天免疫系统的吞噬细胞，特别是巨噬细胞，形成了 防御细菌感染，并配备强大的机制来限制细菌生长和 铲除入侵者。巨噬细胞除了具有直接的抗微生物活性外，还能启动和塑造 强烈的炎症反应，极大地影响疾病。然而，细菌病原体具有 进化的机制来阻止吞噬细胞的这些杀伤机制，并在人体组织中持续存在。 事实上，结核分枝杆菌(Mtb)引发的炎症途径--病原学 人类毁灭性疾病结核病的诱因和项目1的重点--努力促进 细菌生长和结核病。然而，决定结果的宿主基因和细胞途径 感染的原因尚不完全清楚。越来越多的证据表明，结核分枝杆菌与两个 非常不同的肺巨噬细胞亚群，肺泡巨噬细胞和“招募的”巨噬细胞是肺结核的关键 但我们对肺泡巨噬细胞对结核分枝杆菌的反应的了解有限，因为 研究这些驻留在组织中的肺巨噬细胞有困难。在项目1中，我们将使用新的细胞模型 肺泡巨噬细胞与识别特定分子的无偏见的系统方法相结合 这些不同类型的巨噬细胞的潜在感染网络。与技术合作 核心，我们将使用这些信息来预测细菌的传染性，并在人体上进行测试 以迭代的方式对感染样本和小鼠模型进行建模，以模拟感染期间的宿主反应。 这些成果，以及项目2的成果，将由数据管理和生物信息学和 利用现有组学和人类GWAS数据集对岩心进行建模，以识别 与临床发病机制密切相关。重要的是，我们将把功能测试重点放在路径上 在细菌和病毒反应之间共享的(项目2)，以了解导致 在细菌和病毒共同感染期间的协同作用。

PROJECT 1: IDENTIFICATION OF HOST AND BACTERIAL PATHWAYS THAT CONTROL TB PATHOGENESIS IN HUMANS SUMMARY Phagocytes of the mammalian innate immune system, in particular macrophages, form the first line of defense upon bacterial infection and are armed with powerful mechanisms to limit bacterial growth and eradicate invaders. In addition to having direct antimicrobial activity, macrophages also initiate and shape powerful inflammatory responses that dramatically influence disease. Bacterial pathogens, however, have evolved mechanisms to thwart these killing mechanisms of phagocytes, and to persist in human tissues. Indeed, the inflammatory pathways robustly elicited by Mycobacterium tuberculosis (Mtb) – the etiological agent of the devastating human disease tuberculosis (TB) and the focus of Project 1 – work to promote bacterial growth and TB disease. However, the host genes and cellular pathways that dictate the outcome of infection are not entirely clear. There is growing evidence that the earliest interactions of Mtb with two very different subsets of lung macrophages, alveolar and “recruited” macrophages, are critical for TB control, but our understanding of the response of alveolar macrophages to Mtb has been limited due to the difficulty in studying these tissue resident lung macrophages. In Project 1, we will use new cellular models of alveolar macrophages coupled with unbiased, systematic approaches to identify the specific molecular networks that underly infection of these different macrophage types. In collaboration with the Technology Core, we will use this information to make predictions about bacterial infectivity that will be tested in human samples and mouse models of infection in an iterative fashion to model host response during infection. These results, and those from Project 2, will be integrated by the Data Management and Bioinformatics and Modeling Cores with existing -omics and human GWAS datasets to identify host and bacterial signatures that correlate significantly with clinical pathogenesis. Importantly, we will focus our functional testing on pathways that are shared between bacterial and viral responses (with Project 2) to understand the mechanisms that lead to synergies during bacterial-viral co-infection.