THWART-TB : Testing Health Workers At Risk to advance our understanding of TB infection

THWART-TB：对处于危险中的卫生工作者进行检测，以增进我们对结核病感染的了解

• 批准号: 10471574
• 负责人: Ruvandhi Nathavitharana
• 金额: $ 118.95万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-16 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10471574
• 关键词: Address; Antibody Response; Bacteriophages; Biological Assay; Blood specimen; C-reactive protein; CD34 gene; Cause of Death; DNA; Data; Decision Making; Detection; Diagnosis; Disease; Early identification; Evaluation; Exposure to; Fc Receptor; Health; Immune response; Immunoglobulin G; Individual; Infection; Interdisciplinary Study; Interferon Type II; International; Knowledge; Life; Longitudinal cohort study; Measures; Mission; Mycobacterium tuberculosis; National Institute of Allergy and Infectious Disease; Occupational; Peripheral Blood Mononuclear Cell; Persons; Populations at Risk; Predictive Value; Prevention strategy; RNA; Research; Risk; South Africa; South African; Testing; Time; Tuberculosis; biosignature; chronic infection; cohort; high risk; high risk population; immune clearance; improved; infection risk; novel; preference; progression risk; prospective; receptor binding; response; risk stratification; screening

PROJECT SUMMARY Tuberculosis (TB) remains a leading infectious cause of death globally. 1.7 billion people worldwide are estimated to have been infected with TB (LTBI); yet TB infection remains poorly understood. Current LTBI tests cannot distinguish between current infection versus a persistent immune response to a cleared infection and have a low predictive value to identify which people are at risk of developing incident active TB disease. We propose to establish a prospective longitudinal cohort study of health workers (HWs) in Cape Town, South Africa, where our preliminary data reveals HWs have a high annual TB infection risk (34%). This cohort, who will undergo frequent serial evaluation (every 3 months) with a combination of novel assays never previously evaluated together, presents a unique opportunity to evaluate immune responses at the time of initial infection and to characterize the dynamic profile of these immune responses over time in a high-risk population. This interdisciplinary study addresses three knowledge gaps: 1) We will evaluate serial interferon gamma release assay (IGRA) responses to identify early TB infection and characterize the dynamics of IGRA conversion and reversion, which will contribute to understanding of transient versus persistent infection. Furthermore we will elicit HW preferences regarding serial LTBI testing strategies and decision making that will inform the implementation of HW TB screening, which is urgently needed given their occupational TB risk. 2) We will evaluate the temporal dynamics of immune responses to TB by measuring serial RNA biosignatures, C-reactive protein, and Mycobacterium tuberculosis (Mtb)-antibody responses. We will determine whether biosignature results are persistently elevated or wane over time and how these correlate with other measures of immune response. We will be able to comprehensively profile changes in Mtb-antibody responses by not only quantifying IgG levels but by evaluating all isotypes, subclasses and Fc-receptor binding profiles. 3) We will evaluate serial blood samples for detectable Mtb, based on testing of CD34-positive PBMCs and a phage-based assay (Actiphage). Comparing novel Mtb DNA detection approaches could enhance understanding and risk stratification for incident TB in high-risk populations. Our novel data on Mtb immune responses and Mtb quantification in people with LTBI will improve understanding of the correlates of TB immune clearance versus persistence and could help to identify individuals at a higher risk of progression. This study is aligned with the NIAID mission to ‘advance the understanding and diagnosis of re-emerging diseases such as TB’ and to ‘develop international research capacity to respond appropriately to re-emerging disease threats’.

项目摘要 结核病（TB）仍然是全球17亿人的主要感染原因。 据估计，全球感染了TB（LTBI）； 理解的。 对清除感染的免疫反应，并且具有低预测价值以识别哪些人 有发生活动性结核病的风险。 在南非开普敦的卫生工作者纵向研究（HWS），我们 初步数据表明，HWS年度TB感染风险很高（34％）。 与新的测定法相结合，经常进行连续评估（每3个月一次） 先前对共同评估，提出了一种独特的开放性，以评估免疫反应 初始感染的时间并表征免疫反应的动态特征 随着时间的流逝，这项实习生的研究增加了三个知识差距： 1）我们将评估串行干扰素伽马释放分析（IGRA）响应以识别早期结核病 感染并表征IGRA对话和回归的动态，这将有助于 了解转移与持续感染。 关于系列LTBI测试策略和决策的偏好，这些策略将告知 HW TB筛选的实施，鉴于其职业结核病风险，这是迫切需要的。 2）我们将通过测量串行来评估免疫反应的时间动态 RNA生物签名，C反应蛋白和结核分枝杆菌（MTB） - 抗体 我们将确定生物签名结果是否持续升高 随着时间的流逝以及这些与其他免疫反应措施的相关性。 MTB抗体响应中的综合分布不仅可以通过量化水平来改变 但是，通过评估所有同种型，亚类和FC受体结合曲线。 3）我们将根据CD34阳性的测试评估可检测到的串行血液样品MTB PBMC和基于噬菌体的测定法（Actiphage）。 可以增强高风险人群中发病人结核病的理解和风险分层。 我们有关LTBI患者MTB免疫反应和MTB定量的新数据将改善 了解结核病免疫清除与持久性的相关性，并可能有助于 确定该研究的高风险。 “提高对重新培养疾病（例如结核病）的理解和诊断”和“发展” 国际研究能力适当地应对重新出现疾病威胁的能力。