Bacterial and Host Heterogeneity in TB latency, persistence and progression

摘要--总体 直到最近，结核病(TB)一直被视为一种经过几个不同阶段发展的疾病， 主要包括一段感染期，然后是活动性结核病或潜伏期 重新激活的可能性。同样，结核病的病原体结核分枝杆菌(Mtb)一直被 被认为是一种相对稳定的细菌，几乎没有基因组多样性，抗生素耐药性的原因是可以预测的， 以及在培养过程中和感染宿主内的表型一致性。然而，最近的发现，许多 在该应用程序成员的带头下，已经开始在结核病中发现意想不到的异质性 疾病状态、寄主反应、细菌的基因类型和表型，以及明显的克隆 结核分枝杆菌感染人群。这项计划的前提是结核病感染的异质性结果 治疗是由异质宿主细菌转录和转录之间的相互作用决定的 新陈代谢计划。寄主和细菌可能在表型或遗传上被预先编程以从 结核感染到结核病；迅速或缓慢；以及是否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互动的另一个结果，这可能会导致 导致疾病恶化和包括复发在内的不良治疗结果。药物耐受性或耐药性是另一个原因 这些相互作用的结果可能对治疗反应产生广泛影响。尽管Mtb-host和 MTB与药物的相互作用似乎是无关的，我们还将研究免疫和药物耐受的可能性 结核分枝杆菌共享许多转录和代谢程序；因此，也共享一些相同的程序 可以提供治疗靶点的漏洞。该计划由4个项目和3个核心组成，将 在以下具体目标中完成：1)确定细菌和寄主异质性对 在家庭中近距离接触结核病和活动性结核病的表现、进展和后果。 项目1：疾病进展、表现和后果的细菌和宿主决定因素 结核病。2)揭示感染的宿主不同临床结局的免疫学机制 结核分枝杆菌高、低传播株。项目2：结核分枝杆菌病程的免疫决定因素 感染和疾病。3)确定诱导药物耐受的宿主免疫途径，并确定潜在的 治疗干预的途径。在项目3：最大限度地减少结核病体内药物耐受诱导中解决了问题。4) 确定导致药物耐受性异质性表达的细菌因子并鉴定 与不良治疗结果有关。在项目4.药物耐受性、细菌异质性和 结核病治疗结果不良。

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.