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

摘要-项目1 从历史上看，结核病的特点是一个两阶段的过程-感染和疾病。现在很清楚， 感染，重要的是，一旦感染，进展为结核病的可能性是异质的，并随 时间我们现在建议在人体研究中解决细菌和宿主异质性如何改变 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 结核病的表现和后遗症。在细菌方面，来自指示病例的结核分枝杆菌菌株可能是 基于以下的比例被二分为高透射（Mtb-HT）和低透射（Mtb-LT）： 接触TST+的家庭接触者。Mtb-HT与进展至 胸部X光片显示有更多的空洞。至于主机的异质性，我们排除了签名的风险， 标记是宿主对Mtb的免疫应答的内在差异的代表。在南非，ACS- COR特征与亚临床TB的PET-CT扫描结果具有良好的相关性。至于短期和长期- 在巴西，我们描述了与免疫相关的转录标记PREDICT 29， 预测结核病进展的反应。我们将在一个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，以将Mtb-HT感染风险划分为 索引病例的免疫病理学（例如空洞和随后的肺损伤）， HHC、PREDICT 29和共病的修饰作用以及沿着 从LTBI到TB。具体目的是确定Mtb菌株表型（例如Mtb-HT v Mtb-LT）和宿主异质性（进展特征风险、合并症）：1。阶段分布 暴露于HHC的Mtb感染和疾病的比例：表达PREDICT 29的MTBI比例， 进展标志; ACS-COR，炎症标志;亚临床TB和活动性TB; 2.风险和 从MTBI进展到TB的时间和3.肺疾病的程度和性质（如空洞）， 结核病指数病例;炎症持续时间;以及随之而来的肺功能损害。 这些研究可以允许个体化的诊断方法，预防性治疗的目标， 治疗活动性结核病。它们与项目2和临床核心协同作用，提供PBMC和BAL， 充分表征的人群，这将允许确定本研究中发现的免疫学基础。 项目1;以及与项目3合作，提供已知在传播和发病机制方面不同的临床结核分枝杆菌分离株 研究宽容。

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.