Host Pathogen Variation & TB Pathogenesis

控制结核病（TB）的障碍包括开发高效疫苗， 传播和感染的流行地区，并发现药物治疗方案， 杀死巨噬细胞内的休眠细菌。暴露于结核分枝杆菌（Mtb）后， 广泛包括耐药性、无症状潜伏感染、活动性肺病和播散性 感染，包括结核性脑膜炎（TBM）。这种异质性使临床治疗决策复杂化， 注意选择药物的数量和治疗时间。这种广泛的临床谱也呈现出 一个独特的机会，了解控制结核病发病机制的生物机制。一个主要 异质性的来源是人类和结核分枝杆菌的遗传变异的组合， 恒定选择压力。我们的总体计划目标是利用遗传学，基因组学，蛋白质组学， 生物信息学策略，以发现宿主和病原体的基因和基因产物的变异， 与TB临床结果相关，并确定这些变异如何相互作用以调节分子， 细胞和体内功能。我们的战略以越南和乌干达的两个强大队伍为基础 (Core A）捕获了对传统LTBI（潜伏性TB感染）、LTBI、肺结核、肺结核和肺结核的全部抗性谱。 结核病和结核分枝杆菌病形式的播散性疾病。核心A检查配对宿主和Mtb遗传 数据以及与这些不同临床结果的关联。在项目1中，我们使用基因和新的 蛋白质组学策略，以检查Mtb基因和由核心A鉴定的变体如何发挥功能，以及 编码的蛋白质与巨噬细胞反应相互作用并调节巨噬细胞反应。在项目2中，我们使用人类基因 方法沿着巨噬细胞中的蛋白质组学策略，以揭示调节宿主基因和变体， 与耐结核分枝杆菌感染和/或播散性结核病有关。在项目3中，我们研究了体内 归因于特定宿主基因和途径的传播和传播机制， MTB变种，采用一种新的和强大的小鼠感染模型，重现了许多 人类结核病的表现。核心B使用路径驱动和新颖的生物信息学方法， 将核心A的遗传结果与多个大规模和多样化的数据集集成， 识别并优先考虑用于功能测试的途径和蛋白质网络。这一跨学科的 计划和策略将使我们能够测试我们的总体假设，即结核分枝杆菌和宿主基因的变异决定了 异质性临床结果和编码因子与先天免疫细胞相互作用并改变先天免疫细胞。我们将 使用遗传学、基因组学、蛋白质组学和生物信息学策略来检查结核分枝杆菌及其配对的变异， 研究人类宿主对感染和疾病抵抗力和易感性的机制， 用于临床管理和新型免疫调节疗法的生物标志物。

Hurdles for controlling tuberculosis (TB) include developing a highly efficacious vaccine, preventing transmission and infection in endemic areas, and discovering drug treatment regimens that work rapidly and kill dormant bacilli within macrophages. After exposure to Mycobacterium tuberculosis (Mtb), outcomes vary widely including resistance, asymptomatic latent infection, active pulmonary disease, and disseminated infections including TB meningitis (TBM). This heterogeneity complicates clinical treatment decisions with regards to choosing the number of drugs and duration of treatment. This broad clinical spectrum also presents a unique opportunity for understanding the biological mechanisms that control TB pathogenesis. A major source of heterogeneity is a combination of genetic variation in both humans and Mtb that are evolving under constant selective pressure. Our overall program objective is to use genetic, genomic, proteomic, and bioinformatic strategies to discover host and pathogen variants of genes and gene products that are associated with TB clinical outcomes and to determine how these variants interact to regulate molecular, cellular, and in vivo functions. Our strategy is anchored upon two powerful cohorts in Vietnam and Uganda (Core A) that capture the full spectrum of resistance to traditional LTBI (latent TB infection), LTBI, pulmonary TB disease, and disseminated disease in the form of TBM. Core A examines paired host and Mtb genetic data and the association with these diverse clinical outcomes. In Project 1, we use genetic and new proteomic strategies to examine how the Mtb genes and variants identified by Core A function and how the encoded proteins interact with and regulate macrophage responses. In Project 2, we use human genetic methods along with proteomic strategies in macrophages to uncover regulatory host genes and variants that are associated with resistance to Mtb infection and/or disseminated TB. In Project 3, we examine in vivo mechanisms of transmission and dissemination that are attributed to specific host genes and pathways and Mtb variants, employing a new and powerful mouse model of infection that recapitulates many of the manifestations that occur in human TB. Core B uses pathway-driven and novel bioinformatics approaches to integrate the genetic results from Core A with the multiple large-scale and diverse datasets to dynamically identify and prioritize pathways and protein networks for functional testing. Together, this multidisciplinary program and strategy will enable us to test our overall hypothesis that variants of Mtb and host genes dictate heterogeneous clinical outcomes and encode factors that interact with and alter innate immune cells. We will use genetic, genomic, proteomic, and bioinformatic strategies to examine variation in Mtb and its paired human host to examine mechanisms of resistance and susceptibility to infection and disease with discovery of biomarkers for clinical management and novel immunomodulatory therapies.