Bacterial and Host Heterogeneity in TB latency, persistence and progression

摘要-总体 直到最近，结核病（TB）一直被认为是一种疾病，进展在几个离散的阶段， 主要包括感染期，随后是活动性结核病或潜伏状态， 重新激活的可能性。类似地，结核病的病原体结核分枝杆菌（Mtb）已经被发现。 被认为是一种相对稳定的细菌，几乎没有基因组多样性，可预测的抗生素耐药性原因， 以及在培养期间和在其感染宿主内的表型一致性。然而，最近的调查结果显示，许多 由该应用程序的成员带头，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，以及明显的克隆 感染Mtb的人群。该项目的前提是，结核病感染的异质性结果 和处理是由异质宿主细菌转录和 代谢程序宿主和细菌可能在表型上或遗传上预先编程， 结核病感染到结核病;并迅速或缓慢地这样做;并且，有或没有广泛的炎症和肺 损害免疫耐受、逃避或破坏可能是这些相互作用的另一个结果， 恶化的疾病和不良的治疗结果，包括复发。药物耐受性或耐药性是另一个 这些相互作用的结果可能对治疗反应产生广泛影响。虽然Mtb-host和 结核病药物相互作用似乎是无关的，我们也将研究免疫和药物耐受的可能性， 结核分枝杆菌有许多共同的转录和代谢程序，因此，也有一些相同的 可以提供治疗靶点的弱点。该计划由4个项目和3个核心组成， 具体目的如下：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。 在项目1中解决：细菌和宿主的进展决定因素， TB. 2)为了揭示宿主感染后不同临床结果的免疫学机制， 结核分枝杆菌高、低传播株项目2：结核病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中解决：最大限度地减少结核病的体内药物耐受性诱导。四、 确定导致耐药性异质性表达的细菌因素， 与不良治疗结果有关。在项目4中。耐药性、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.