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: 10493271
• 负责人: Jerrold J. Ellner
• 金额: $ 42.93万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10493271
• 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，结核病被描述为一个两个阶段的过程--感染和疾病。现在很明显， 感染和重要的是，一旦感染后发展为结核病的可能性是不同的，并且不同 时间到了。我们现在建议在人类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的结核病感染阶段分布、进展风险和 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 根据以下比例分为高透射率(Mtb-HT)和低透射率(Mtb-LT 暴露的家庭接触者为TST+。MTB-HT与更大的进展风险相关 疾病和胸部X光片上更多的空洞。关于宿主的异质性，我们假设签名的风险 签名代表了宿主对结核分枝杆菌免疫反应的内在差异。在南非，ACS- COR征象与亚临床结核的PET-CT扫描表现有较好的相关性。至于短线和长线- 进展的长期风险，在巴西，我们描述了与免疫相关的转录签名PREDICT29 预测进展为结核病的反应。我们将在未来队列中使用家庭联系模型 乌干达和乌干达和巴西的回溯性队列将感染Mtb-HT的风险划分为 指示病例的免疫病理学(如空洞和随后的肺损伤)，感染力较大 HHC、PREDICT29的修饰效应和共病，以及沿着 从LTBI到TB的光谱。具体目的是确定Mtb菌株表型的影响(例如Mtb-HTv MTB-LT)和宿主异质性(进展的风险信号，共病)：1.分期的分布 暴露于HHC中结核分枝杆菌感染和疾病的关系：MTBI中表达PREDICT29的比例， 进展信号；ACS-COR，炎性信号；亚临床结核和活动性结核；2.风险和 从MTBI进展到结核病的时间和3.年内肺部疾病的范围和性质(如空洞) 结核病指标病例；炎症持续时间；以及随之而来的肺功能损害。 这些研究可以使个性化的诊断方法、预防性治疗的靶向以及 活动性肺结核的治疗。他们与项目2和临床核心协同工作，从 特征良好的人群，将允许确定在这一发现的免疫学基础 项目1；与项目3合作，提供已知在传播和发病机制上不同的临床结核分枝杆菌分离株 用于研究耐受性。