Host Pathogen Variation & TB Pathogenesis

控制结核病(TB)的障碍包括开发高效疫苗，预防 流行地区的传播和感染，以及发现见效迅速和 杀死巨噬细胞内的休眠细菌。暴露于结核分枝杆菌(Mtb)后，结果各不相同 广泛包括耐药性、无症状潜伏感染、活动性肺部疾病和播散性 感染包括结核脑膜炎(TBM)。这种异质性使临床治疗决策复杂化 关于选择药物的数量和疗程。这一广泛的临床谱系也呈现出 这是一个了解控制结核病发病的生物学机制的独特机会。一位少校 异质性的来源是人类和结核分枝杆菌的遗传变异的组合，这些变异在 恒定的选择压力。我们的总体计划目标是使用遗传、基因组、蛋白质和 发现寄主和病原体变异的基因和基因产物的生物信息学策略 与结核病临床结果相关，并确定这些变异如何相互作用来调节分子， 细胞功能和体内功能。我们的战略建立在越南和乌干达两个强大的同伙基础上 (核心A)捕获对传统LTBI(潜伏性结核病感染)、LTBI、肺脏的全部耐药性 结核病，以及以结核分枝杆菌形式传播的疾病。核心A检查配对宿主和结核分枝杆菌基因 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Genetic和New 蛋白质组学策略研究结核分枝杆菌基因和由核心A识别的变异是如何发挥作用的，以及如何 编码的蛋白质与巨噬细胞反应相互作用并调节。在项目2中，我们使用了人类基因 方法以及巨噬细胞中的蛋白质组策略，以发现调节宿主基因和变体 与对结核分枝杆菌感染和/或播散性结核病的耐药性有关。在项目3中，我们在体内检查 传播和传播机制，归因于特定的宿主基因和途径 MTB变种，采用了一种新的强大的小鼠感染模型，该模型概括了许多 在人类结核病中出现的表现。核心B使用路径驱动和新的生物信息学方法来 将核心A的遗传结果与多个大规模、多样化的数据集进行动态集成 确定用于功能测试的通路和蛋白质网络并确定其优先顺序。总而言之，这一多学科 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 不同的临床结果和编码与先天免疫细胞相互作用和改变的因素。我们会 使用遗传、基因组、蛋白质和生物信息学策略检查结核分枝杆菌及其配对的变异 人类宿主检查对感染和疾病的抵抗力和易感性的机制 临床治疗和新的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.