Host Pathogen Variation & TB Pathogenesis

宿主病原体变异

• 批准号: 10271168
• 负责人: JEFFERY S COX
• 金额: $ 263.89万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10271168
• 关键词: Area; Bacillus; Bioinformatics; Biological; Cells; Clinical; Clinical Management; Clinical Treatment; Data; Data Management Resources; Data Set; Disease; Exposure to; Genes; Genetic; Genetic Variation; Genomics; Heterogeneity; Human; Human Genetics; Immune; Immune system; Infection; Integration Host Factors; Lung diseases; Medical Genetics; Meningeal Tuberculosis; Meningitis; Methods; Modeling; Molecular; Mus; Mycobacterium tuberculosis; Outcome; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Predisposition; Prevention strategy; Process; Proteins; Proteomics; Pulmonary Tuberculosis; Resistance; Resistance to infection; Source; Testing; Treatment Protocols; Tuberculosis; Uganda; Vaccines; Variant; Vietnam; Work; biomarker discovery; clinical phenotype; cohort; experimental study; follow-up; gene product; genetic information; genetic variant; genome-wide; human pathogen; immunomodulatory therapies; in vivo; innovation; insight; latent infection; macrophage; mouse model; multidisciplinary; multiple omics; novel; novel marker; pathogen; pressure; prevent; programs; protein function; resistance mechanism; response; synergism; transcriptome sequencing; transmission process; treatment duration; treatment strategy

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.

控制结核病（TB）的障碍包括开发高效的疫苗，防止 流行地区的传播和感染，发现迅速起作用的药物治疗方案 杀死巨噬细胞中休眠的杆菌。暴露于结核分枝杆菌（MTB）后，结果有所不同 广泛包括阻力，无症状的潜在感染，活动性肺部疾病和弥散 包括结核病（TBM）在内的感染。这种异质性使临床治疗决策复杂化 选择药物数量和治疗持续时间。这个广泛的临床光谱也呈现 理解控制结核病发病机制的生物学机制的独特机会。专业 异质性的来源是人类和MTB遗传变异的结合 恒定的选择压力。我们的整体程序目标是使用遗传，基因组，蛋白质组学和 发现基因和基因产物的宿主和病原体变异的生物信息学策略 与结核病临床结果相关，并确定这些变体如何相互作用以调节分子， 细胞和体内功能。我们的策略基于越南和乌干达的两个强大队列 （核心A）捕获对传统LTBI（潜在结核病感染），LTBI，肺部的全部抵抗力 结核病疾病和以TBM形式传播的疾病。核心A检查配对宿主和MTB遗传 数据和与这些不同的临床结果的关联。在项目1中，我们使用遗传和新 蛋白质组学策略，以检查MTB基因和变体如何通过核心A识别功能以及如何 编码的蛋白质与并调节巨噬细胞反应。在项目2中，我们使用人类遗传 方法以及巨噬细胞中的蛋白质组学策略，以发现调节性宿主基因和变体 与对MTB感染和/或传播结核病的抗性有关。在项目3中，我们检查体内 传播和传播机制归因于特定的宿主基因和途径，以及 MTB变体采用一种新的强大的鼠标感染模型，该模型概括了许多 人类结核病中发生的表现。核心B使用途径驱动和新颖的生物信息学方法 将核心A与多个大规模和不同数据集的遗传结果整合到动态 确定并确定途径和蛋白质网络进行功能测试。在一起，这个多学科 计划和策略将使我们能够检验我们的整体假设，即MTB和宿主基因的变体决定 异质临床结果和编码与先天免疫细胞相互作用并改变先天免疫细胞的因子。我们将 使用遗传，基因组，蛋白质组学和生物信息学策略检查MTB及其配对的变异 人类宿主检查耐药性和对感染和疾病易感性的机制，并发现 用于临床管理和新型免疫调节疗法的生物标志物。