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: 10271648
• 负责人: Jerrold J. Ellner
• 金额: $ 39.19万
• 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/10271648
• 关键词: Address; Aerosols; Bacteria; Brazil; Categories; 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; Positron-Emission Tomography; 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; base; comorbidity; design; fluorodeoxyglucose; immunopathology; indexing; infection risk; lung injury; metabolomics; microbial; personalized approach; predicting response; pulmonary function; respiratory; 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，结核病已被视为一个两阶段的过程 - 感染和疾病。现在很明显 感染，重要的是，曾经进展到结核病的可能性是异质的，并且有各种 时间。我们现在建议在人类研究中解决细菌和宿主异质性如何修改 与结核病病例密切接触后结核病感染阶段的分布，进展的风险和 结核病疾病的表现和后遗症。在细菌一侧，索引病例的MTB菌株可能是 基于比例 暴露于TST+的家庭接触。 MTB-HT与更大的发展风险有关 疾病和胸部X射线的更多空化。关于主机异质性，我们阳性签名风险 签名是宿主免疫反应MTB的内在差异的代理。在南非，ACS- COR签名是亚临床结核病PET-CT扫描发现的良好相关性。关于短期 在巴西，进展的术语风险，我们表征了一个与免疫相关的转录签名预测29 反应预测了对结核病的进展。我们将在预期队列中使用家庭联系模型 在乌干达和巴西的乌干达和回顾性队列，以MTB-HT感染的风险 索引病例的免疫病理学（例如，空化和随后的肺损害），更大的感染力 HHC，预测29和合并症的修改作用，以及沿着 从LTBI到TB的频谱。具体目的是确定MTB应变表型的影响（例如MTB-HT V MTB-LT）和主机异质性（进展特征的风险，合并症）：1。阶段分布 暴露于HHC中的MTB感染和疾病：表达预测的MTBI的比例29 进展标志； ACS-COR，炎症签名；亚临床结核和主动结核； 2。风险和 从mtbi到结核病和3的进展时间。 结核病指数案例；炎症的持续时间；以及随之而来的肺功能受损。 这些研究可以允许个性化的诊断方法，靶向预防疗法以及 主动结核病的处理。它们与项目2和临床核心协同作用，以提供PBMC和BAL 特征良好的人群将允许确定该发现的免疫学基础 项目1;并提供项目3提供临床MTB分离株已知的传播和发病机理不同 用于研究耐受性。