Bacterial and Host Heterogeneity in TB latency, persistence and progression

摘要 - 总体 直到最近，结核病 (TB) 还被视为一种经过几个不同阶段进展的疾病， 主要包括一段感染期，随后是活动性结核病或潜伏期 重新激活的潜力。同样，结核病的病原体结核分枝杆菌 (Mtb) 已被 被视为一种相对稳定的细菌，基因组多样性很少，抗生素耐药性的原因可预测， 以及培养期间和感染宿主内的表型一致性。然而，最近的调查结果显示，许多 由该应用程序成员带头，已经开始发现结核病中意想不到的异质性 疾病状态、宿主反应、细菌的基因型和表型，以及明显克隆的细菌 结核分枝杆菌感染人群。该计划的前提是结核病感染的异质性结果 治疗方法是由异质宿主细菌转录和转录之间的相互作用决定的 代谢计划。宿主和细菌可以在表型或遗传上进行预编程，以从 结核感染导致结核病；并快速或缓慢地进行；并且，有或没有广泛的炎症和肺部 损坏。免疫耐受、逃避或颠覆可能是这些相互作用的另一个结果，这可能导致 疾病恶化和不良治疗结果（包括复发）。药物耐受性或耐药性是另一个问题 这些相互作用的结果可能对治疗反应产生广泛的影响。尽管 Mtb 主机和 Mtb-药物相互作用似乎是不相关的，我们还将研究免疫和耐药性的可能性 Mtb 共享许多转录和代谢程序；因此，也分享一些相同的 可以提供治疗靶点的脆弱性。该计划由 4 个项目和 3 个核心组成 完成以下具体目标：1）确定细菌和宿主异质性对 家庭中密切接触结核病和活动性结核病的表现、进展和后果。 项目 1 中涉及：细菌和宿主的进展、表现和后果的决定因素 结核病。 2）揭示感染宿主不同临床结果的免疫学机制 Mtb 的高和低传播菌株。项目 2 中涉及：结核病病程的免疫决定因素 感染和疾病。 3) 确定诱导耐药性的宿主免疫途径并识别潜在的 治疗干预的途径。项目 3 中提出：最大限度地减少结核病的体内耐药性诱导。 4） 定义导致耐药性异质表达的细菌因素并表征 与不良治疗结果的联系。项目 4 中提出。药物耐受性、细菌异质性和 不良结核病治疗结果。

ABSTRACT - OVERALL Until recently, Tuberculosis (TB) has been viewed as a disease that progresses over several discrete stages, principally consisting of a period of infection followed by either active TB disease or a latent state with the potential for reactivation. Similarly, Mycobacterium tuberculosis (Mtb), the causative agent of TB, has been viewed as a relatively stable bacterium with little genomic diversity, predictable causes of antibiotic resistance, and phenotypic uniformity both during culture and within its infected host. However, recent findings, many spearheaded by the members of this application, have begun to discover unexpected heterogeneity in TB disease states, host responses, the genotypes and phenotypes of the bacteria, and among the apparently clonal infecting population of Mtb. The premise for this program is that the heterogenous outcomes of TB infections and treatments are determined by the interplay between heterogeneous host-bacteria transcriptional and metabolic programs. Host and bacteria may be pre-programmed phenotypically or genetically to progress from TB infection to TB disease; and to do so rapidly or slowly; and, with or without extensive inflammation and lung damage. Immune tolerance, evasion or subversion may be another result of these interactions, which could lead to worsening disease and adverse treatment outcomes including relapse. Drug tolerance or resistance is another result of these interactions that may have widespread effects on treatment responses. Although Mtb-host and Mtb-drug interactions would seem to be unrelated, we will also study the possibility that immune and drug tolerant Mtb share a number of transcriptional and metabolic programs; and thus, also share some of the same vulnerabilities that could provide therapeutic targets. Consisting of 4 Projects and 3 Cores, this program will be accomplished in the following Specific Aims: 1) To determine the effects of bacterial and host heterogeneity on the manifestations, progression and consequences of close exposure to TB in the household, and of active TB. Addressed in Project 1: Bacterial and Host Determinants of Progression, Manifestations and Consequences of TB. 2) To uncover the immunological mechanisms underlying the diverse clinical outcomes in hosts infected with high and low transmission strains of Mtb. Addressed in Project 2: Immune Determinants of the Course of Mtb infection and Disease. 3) To define the host immune pathways that induce drug tolerance and identify potential routes to therapeutic intervention. Addressed in Project 3: Minimizing in vivo Drug Tolerance Induction in TB. 4) To define bacterial factors that contribute to the heterogeneous expression of drug tolerance and characterize links with adverse treatment outcomes. Addressed in Project 4. Drug Tolerance, Bacterial Heterogeneity and Adverse TB Treatment Outcomes.