Bacterial and Host Heterogeneity in TB latency, persistence and progression

结核潜伏期、持续性和进展的细菌和宿主异质性

• 批准号: 10271644
• 负责人: David Alland
• 金额: $ 275.15万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10271644
• 关键词: Address; Aftercare; Antibiotic Resistance; Bacteria; Behavior; Cells; Clinical; Complex; Disease; Drug Exposure; Drug Interactions; Drug Tolerance; Drug resistance; Effectiveness; Exposure to; Genetic; Genetic Transcription; Genomics; Genotype; Goals; Heterogeneity; Household; Human; Immune; Immune Tolerance; Immune response; Immunity; Immunologics; Individual; Infection; Inflammation; Laboratories; Lead; Link; Metabolic; Mycobacterium tuberculosis; Outcome; Participant; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Population; Population Heterogeneity; Recurrent disease; Relapse; Route; Sampling; Systems Biology; Testing; Therapeutic; Therapeutic Intervention; Treatment outcome; Tuberculosis; Work; analytical tool; clinical phenotype; design; in vivo; latent infection; lung injury; member; mouse model; novel; novel therapeutics; pathogen; prevent; programs; response; therapeutic target; trait; transmission process; treatment response; treatment trial; tuberculosis treatment

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.

摘要 - 总体 直到最近，结核病（TB）仍被视为在几个离散阶段发展的疾病， 主要由感染期间，然后是活性结核病或潜在状态 重新激活的潜力。同样，结核分枝杆菌（MTB）是结核病的致病药物 被视为一种相对稳定的细菌，具有很少的基因组多样性，可预测的抗生素耐药性原因， 在培养物和感染宿主中，以及表型均匀性。但是，最近的发现，许多 由本申请成员带头，已经开始发现结核病的意外异质性 疾病状态，宿主反应，细菌的基因型和表型以及明显的克隆中 感染MTB的种群。该程序的前提是结核病感染的异质结果 和治疗是由异质宿主 - 细菌转录和 代谢程序。宿主和细菌可以在表型或遗传上进行预编程以从 结核病感染结核病；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。免疫耐受性，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 加剧疾病和不良治疗结果，包括复发。药物耐受性或抗性是另一种 这些相互作用可能对治疗反应产生广泛影响的结果。虽然MTB主持人和 MTB-Crug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 MTB共享许多转录和代谢程序；因此，也共享一些相同的 可以提供治疗靶标的漏洞。由4个项目和3个核心组成，该程序将是 在以下特定目的中完成：1）确定细菌和宿主异质性对 家庭和主动结核病中TB的紧密暴露的表现，进展和后果。 在项目1中解决：细菌和宿主的进展，表现和后果的决定因素 TB。 2）揭示感染宿主的多种临床结果的背后的免疫机制 MTB的高和低传输菌株。在项目2中解决：MTB过程的免疫决定因素 感染和疾病。 3）定义诱导药物耐受性并识别潜力的宿主免疫途径 治疗干预的路线。在项目3中解决：在结核病中最小化体内药物耐受性诱导。 4） 定义有助于药物耐受性异质表达并表征的细菌因子 与不良治疗结果的联系。在项目4中解决。药物耐受性，细菌异质性和 不良结核病治疗结果。