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

项目摘要 结核病（TB）仍然是全球主要的传染性死亡原因。1.7亿人 据估计，全世界约有100万人感染了结核病（LTBI），但结核病感染率仍然很低。 明白目前的LTBI测试无法区分当前感染与持续感染。 对清除感染的免疫反应，并具有较低的预测值，以确定哪些人 有发生活动性结核病的风险。我们建议建立一个有前景的 对南非开普敦的卫生工作者（HWs）进行了一项纵向队列研究， 初步数据显示，医务工作者每年感染结核病的风险很高（34%）。这群人，谁会 频繁进行系列评价（每3个月一次），结合新的检测方法， 以前一起评估，提供了一个独特的机会，以评估免疫反应， 初始感染的时间，并描述这些免疫应答的动态特征 随着时间的推移，在高风险人群中。这项跨学科研究解决了三个知识差距： 1)我们将评估系列干扰素γ释放试验（IGRA）的反应，以确定早期结核病 感染和特点的动态IGRA转换和逆转，这将有助于 暂时性感染和持续性感染的区别此外，我们将引出HW 关于序列LTBI测试策略和决策的偏好，将告知 实施高危人群结核病筛查，考虑到他们的职业结核病风险，这是迫切需要的。 2)我们将通过测量结核病免疫应答的时间动态， RNA生物特征、C反应蛋白和结核分枝杆菌（Mtb）抗体 应答我们将确定生物特征结果是否持续升高或下降 以及这些指标与其他免疫反应指标的相关性。我们将能够 不仅通过定量IgG水平， 而是通过评估所有同种型、亚类和Fc受体结合谱。 3)我们将根据CD34阳性的检测结果，评估一系列血液样本中可检测到的结核分枝杆菌。 PBMC和基于噬菌体的测定（Actiphage）。新型结核分枝杆菌DNA检测方法的比较 可以加强对高危人群中结核病事件的理解和风险分层。 我们关于LTBI患者Mtb免疫应答和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，并有助于 识别具有更高进展风险的个体。本研究与NIAID的使命一致， “促进对结核病等重新出现疾病的认识和诊断”，并“发展 国际研究能力，以适当应对重新出现的疾病威胁。

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’.