Host Pathogen Variation & TB Pathogenesis

宿主病原体变异

• 批准号: 10653900
• 负责人: JEFFERY S COX
• 金额: $ 259.91万
• 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/10653900
• 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; Macrophage; Meningeal Tuberculosis; Methods; Modeling; Molecular; Multiomic Data; 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; diverse data; experimental study; follow-up; gene product; genetic information; genetic variant; genome-wide; immunomodulatory therapies; in vivo; innovation; insight; latent infection; mouse model; multidisciplinary; 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疫苗、预防结核病 流行地区的传播和感染，并发现快速有效的药物治疗方案 杀死巨噬细胞内休眠的杆菌。接触结核分枝杆菌 (Mtb) 后，结果会有所不同 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，包括结核性脑膜炎 (TBM)。这种异质性使临床治疗决策变得复杂 关于选择药物数量和治疗持续时间。这种广泛的临床谱还呈现 这是了解控制结核病发病机制的独特机会。一个专业 异质性的来源是人类和结核分枝杆菌的遗传变异的组合，这些变异是在 恒定的选择压力。我们的总体计划目标是利用遗传学、基因组学、蛋白质组学和 发现宿主和病原体基因和基因产物变异的生物信息策略 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、 细胞和体内功能。我们的战略基于越南和乌干达的两个强大阵营 （核心 A）捕获对传统 LTBI（潜伏性结核感染）、LTBI、肺结核的全谱耐药性 结核病和以 TBM 形式传播的疾病。核心 A 检查配对宿主和结核分枝杆菌遗传 数据以及与这些不同临床结果的关联。在项目1中，我们使用遗传和新的 蛋白质组学策略，用于检查 Core A 识别的 Mtb 基因和变体如何发挥作用以及 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，我们利用人类基因 方法以及巨噬细胞中的蛋白质组策略来揭示调控宿主基因和变异 与结核分枝杆菌感染和/或播散性结核病的抵抗力有关。在项目 3 中，我们检查体内 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、强大的小鼠感染模型，概括了许多 人类结核病中出现的表现。核心 B 使用通路驱动和新颖的生物信息学方法 将 Core A 的遗传结果与多个大规模且多样化的数据集进行动态整合 识别并优先考虑用于功能测试的途径和蛋白质网络。共同努力，这个多学科 计划和策略将使我们能够检验我们的总体假设，即结核分枝杆菌和宿主基因的变异决定了 异质的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素。我们将 使用遗传、基因组、蛋白质组和生物信息策略来检查 Mtb 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机制，发现 用于临床管理和新型免疫调节疗法的生物标志物。

项目成果

Evolution and transmission of antibiotic resistance is driven by Beijing lineage Mycobacterium tuberculosis in Vietnam.

• DOI: 10.1128/spectrum.02562-23
• 发表时间: 2023-12-12
• 期刊: Microbiology spectrum
• 影响因子: 3.7

Genetic epidemiology of resistance to M. tuberculosis Infection: importance of study design and recent findings.

• DOI: 10.1038/s41435-023-00204-z
• 发表时间: 2023-06
• 期刊: Genes and immunity
• 影响因子: 5

Parallel signatures of Mycobacterium tuberculosis and human Y-chromosome phylogeography support the Two Layer model of East Asian population history.

• DOI: 10.1038/s42003-023-05388-8
• 发表时间: 2023-10-13
• 期刊: COMMUNICATIONS BIOLOGY
• 影响因子: 5.9
• 作者: Silcocks, Matthew;Dunstan, Sarah J.
• 通讯作者: Dunstan, Sarah J.

CD4-mediated immunity shapes neutrophil-driven tuberculous pathology.

CD4 介导的免疫塑造了中性粒细胞驱动的结核病病理。

• DOI: 10.1101/2024.04.12.589315
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Gern,BenjaminH;Klas,JosephaM;Foster,KimberlyA;Cohen,SaraB;Plumlee,CourtneyR;Duffy,FergalJ;Neal,MaxwellL;Halima,Mehnaz;Gustin,AndrewT;Diercks,AlanH;Aderem,Alan;GaleJr,Michael;Aitchison,JohnD;Gerner,MichaelY;Urdahl,K
• 通讯作者: Urdahl,K