Bacterial and host determinants of progression, manifestations and consequences of TB

结核病进展、表现和后果的细菌和宿主决定因素

• 批准号: 10665025
• 负责人: Reynaldo Dietze
• 金额: $ 55.93万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 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/10665025
• 关键词: Address; Aerosols; Bacteria; Brazil; Categories; Classification; Clinical; Diabetes Mellitus; Diagnosis; Disease; Environment; Environmental Risk Factor; Evaluation; Exposure to; Funding; Gene Expression Profile; HIV Infections; Heterogeneity; Household; Human; Immune response; Immunologics; Impairment; Infection; Inflammation; Inflammatory; Integration Host Factors; Lung diseases; Malnutrition; Modeling; Multi-Drug Resistance; Mus; Mycobacterium tuberculosis; Nature; Organism; PET/CT scan; Pathogenesis; Pathogenicity; Patients; Pattern; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Population; Preventive therapy; Process; Prospective cohort; Proxy; Recurrence; Retrospective cohort; Retrospective cohort study; Risk; Side; South Africa; Sputum; Symptoms; Testing; Thoracic Radiography; Time; Tuberculin Test; Tuberculosis; Uganda; active method; comorbidity; design; fluorodeoxyglucose; immunopathology; indexing; infection risk; lung injury; metabolomics; microbial; personalized approach; predicting response; predictive signature; progression risk; pulmonary function; respiratory; synergism; transcriptomics; transmission process

ABSTRACT - PROJECT 1 Historically, TB has been characterized as a two-stage process – infection and disease. It now is clear that infection and importantly the likelihood once infected of progressing to TB is heterogeneous and varies with time. We propose now to address in human studies how bacterial and host heterogeneity modify the distribution of stages of TB infection following close contact with a TB case, the risk of progression and the manifestations and sequelae of TB disease. On the bacterial side, Mtb strains from index cases could be dichotomized into high transmission (Mtb-HT) and low transmission (Mtb-LT) based on the proportion of exposed household contacts that were TST+. Mtb-HT was associated with greater risk of progression to disease and more cavitation on chest X-ray. As regards host heterogeneity, we posit that risk of signature signatures are a proxy for intrinsic differences in the host immune response to Mtb. In South Africa the ACS- COR signature was a good correlate of PET-CT scan findings of subclinical TB. As regards short-and long- term risk of progression, in Brazil, we characterized a transcriptional signature PREDICT29 tied to the immune response that predicted progression to TB. We will use the household contact model in a prospective cohort in Uganda and retrospective cohorts in Uganda and Brazil to partition the risk of infection with Mtb-HT between immunopathology of the index case (eg cavitation and subsequent lung damage), greater force of infection for HHC, the modifying effects of PREDICT29 and co-morbidities, and increased risk of progression along the spectrum from LTBI to TB. Specific Aims are to determine the impact of Mtb strain phenotype (eg Mtb-HT v Mtb-LT) and host heterogeneity (risk of progression signatures, co-morbidities) on: 1. The distribution of stages of Mtb infection and disease in exposed HHC: the proportion of MTBI that express PREDICT29, a risk of progression signature; ACS-COR, an inflammatory signature; subclinical TB and active TB; 2. The risk and timing of progression from MTBI to TB and 3. The extent and nature (eg cavitation) of pulmonary disease in TB index cases; the duration of inflammation; and the consequent impairment in pulmonary function. These studies could permit individualized approaches to diagnosis, targeting of preventive therapy, and treatment of active TB. They synergize with Project 2 and the clinical core in providing PBMC and BAL from well-characterized populations that will allow determination of the immunologic basis for the findings in this Project 1; and with Projects 3 in providing clinical Mtb isolates known to differ in transmission and pathogenesis for study of tolerance.

摘要 - 项目 1 从历史上看，结核病被描述为一个两个阶段的过程——感染和疾病，现在已经很清楚了。 感染，并且一旦感染，进展为结核病的可能性是异质的，并且随着感染的不同而变化 我们现在建议在人类研究中解决细菌和宿主的异质性如何改变。 与结核病例密切接触后结核感染阶段的分布、进展风险和 结核病的表现和后遗症 在细菌方面，指示病例中的结核分枝杆菌菌株可能是结核病的表现和后遗症。 根据比例分为高透射率（Mtb-HT）和低透射率（Mtb-LT） 暴露于 Mtb-HT 的家庭接触者与进展为 Mtb-HT 的风险更大相关。 关于宿主异质性，我们认为存在特征风险。 特征是宿主对 Mtb 免疫反应的内在差异的代表。在南非，ACS- COR 特征与亚临床结核病的 PET-CT 扫描结果具有良好的相关性。 在巴西，我们描述了与免疫相关的转录特征 PREDICT29 我们将在前瞻性队列中使用家庭接触模型。 乌干达以及乌干达和巴西的回顾性队列将 Mtb-HT 感染的风险划分为 指示病例的免疫病理学（例如空洞和随后的肺损伤），感染力更大 HHC、PREDICT29 和合并症的改变作用以及沿疾病进展的风险增加 从 LTBI 到 TB 的谱图 具体目标是确定 Mtb 菌株表型的影响（例如 Mtb-HT v）。 Mtb-LT）和宿主异质性（进展特征风险、共病）： 1. 阶段分布 暴露的 HHC 中 Mtb 感染和疾病的比例：表达 PREDICT29 的 MTBI 比例，这是一种风险 特征；ACS-COR 进展、亚临床结核病和活动性结核病； 从 MTBI 进展为 TB 的时间，以及 3. 肺部疾病的程度和性质（例如空洞） 结核指数病例；炎症持续时间；以及随之而来的肺功能损害。 这些研究可以实现个性化的诊断方法、针对性的预防性治疗以及 它们与项目 2 和提供 PBMC 和 BAL 的临床核心协同作用。 充分表征的人群将有助于确定本研究结果的免疫学基础 项目 1；以及项目 3 提供已知传播和发病机制不同的临床 Mtb 分离株 用于耐受性研究。