Mtb strain-dependent mechanisms of pathogenesis in mouse models

结核病(TB)是一种高度异质性的人类疾病，它发生在一些但不是全部， 吸入1-3个结核分枝杆菌(Mtb)感染杆菌的个人。结核病可以 范围从轻度和自我解决的肺部疾病，到严重的或可以传播到 肺外部位。理解结核病发病机制的复杂性需要一个整体的 整合人类和动物模型研究的方法。尽管有越来越多的证据表明 结核分枝杆菌菌株依赖因素驱动不同的感染结果，体内机制 治理这些结果的人知之甚少。在这个项目中，我们从临床结核分枝杆菌开始。 与不同的致病结果有关(例如，高传播性疾病或传播性疾病) 或在核心A和项目中确定的候选基因发生修改的突变菌株 1、确定结核分枝杆菌菌株的多态与不同的人类临床结局相关。 感染这些临床或突变结核分枝杆菌菌株的小鼠将被用来研究它们是如何 控制发病的三个不同阶段：1)在气雾剂部位建立感染 吸入，2)传播到远处，以及3)与宿主免疫的相互作用 肺巨噬细胞群。这些研究将利用我们小组在以下方面的最新进展 小鼠结核病模型，包括确定气溶胶结核分枝杆菌感染后最早的细胞事件， 使用生理性超低剂量(ULD)感染模型跟踪结核分枝杆菌传播 小鼠感染1-3CFU的雾化结核分枝杆菌，评估配对的宿主和结核分枝杆菌 不同肺巨噬细胞类型的转录本。多参数共焦显微镜 先进的定量图像分析将用于确定这些结核分枝杆菌菌株是如何- 依赖因素影响感染部位的免疫细胞相互作用。该计划的总体目标 建议的实验是为了深入了解发病的分子和细胞机制。 在结核分枝杆菌感染的不同阶段为新的宿主和病原体导向的发展提供信息 干预措施。

Tuberculosis (TB) is a highly heterogeneous human disease that develops in some, but not all, individuals who inhale 1-3 infectious bacilli of Mycobacterium tuberculosis (Mtb). TB disease can range from pulmonary disease that is mild and self-resolving, to severe, or can disseminate to extrapulmonary sites. Understanding the complexity of TB pathogenesis requires a holistic approach that integrates human and animal model studies. Although there is growing evidence that Mtb strain-dependent factors drive different infection outcomes, the in vivo mechanisms that govern these outcomes are poorly understood. In this project, we start with clinical Mtb strains associated with different pathogenic outcomes (e.g., high transmission or disseminated disease) or mutant strains harboring modifications in gene candidates, identified in Core A and Project 1, to identify polymorphisms in Mtb strains associated with distinct human clinical outcomes. Mice infected with these clinical or mutant Mtb strains will be used to investigate how they govern three distinct stages of pathogenesis: 1) establishing infection at the site of aerosol inhalation, 2) dissemination to distant sites, and 3) interactions with host immunity in distinct lung macrophage populations. These studies will leverage our group’s recent advances in mouse TB models, including identifying the earliest cellular events after aerosol Mtb infection, tracking Mtb dissemination using a physiologic, ultra low-dose (ULD) infection model in which mice are infected with 1-3 CFUs of aerosolized Mtb, and assessing paired host and Mtb transcriptomes in distinct pulmonary macrophage types. Multiparameter confocal microscopy and advanced quantitative image analysis will be used to determine how these Mtb strain- dependent factors shape immune cell interactions at infection sites. The overall goal of the proposed experiments is to gain insight into molecular and cellular mechanisms of pathogenesis at distinct stages of Mtb infection to inform development of novel host- and pathogen-directed interventions.