PROgression of Tuberculosis infECTion in young children living with and without HIV: the PROTECT study

项目总结 绝大多数儿童结核病(TB)死亡发生在5岁的儿童中，突显了 确定罹患结核病风险较高的幼儿，并启动预防性治疗。但是，当前 结核分枝杆菌(Mtb)感染检测对结核病进展的预测价值很低。使 针对生物标记物的幼儿结核病预防治疗的进展，迫切需要确定 反映儿童结核病独特发病机制的新宿主标志物可以在病程较早时被检测到 可以更容易地将其转化为护理点化验。《公约》的总体目标 拟议的项目是在符合世界卫生组织标准的幼儿中识别生物标记物签名 世界卫生组织(WHO)-建议的结核病进展测试最低准确度目标。我们假设 反映结核分枝杆菌感染免疫控制失败的儿童结核病宿主生物标志物的子集 将在早期预测幼儿结核病疾病进展方面具有最好的性能。来检查我们的 假设，我们建议利用1)生物储存库，提供访问来自患有癌症的儿童的银行样本 推定为结核病和健康儿童，有和没有暴露于结核病和结核杆菌感染(乌干达、南非、 冈比亚)；2)提供幼儿连续样本的生物库，跟踪12个月或更长时间 突发结核病(乌干达、南非、越南)；3)最先进的平台和生物信息学 多组学生物标记物发现的管道。在目标1中，我们将测量和比较生物标记物水平(宿主 无细胞核糖核酸、蛋白质、代谢物和结核分枝杆菌抗原抗体) 结核病和健康儿童以确定区分儿童结核病的候选宿主生物标志物， 区分结核分枝杆菌感染，结核病与结核分枝杆菌感染的重叠，并将结核分枝杆菌感染分离为 多个子组。在目标2中，我们将使用通径分析、体外人类模型和体内小鼠模型 对与结核分枝杆菌感染的免疫控制相关的候选宿主生物标志物进行优先排序。在《目标3》中， 我们将获得由优先候选宿主生物标记物(S)组成的生物签名，并评估其准确性 用于在独立培训和测试中预测结核病的总体进展和艾滋病毒携带者儿童中的进展。 这些目标的完成将导致识别有希望的生物签名，这些签名可以在 大规模实地研究，并转化为用于预测儿童结核病进展的护理点测试。

PROJECT SUMMARY The vast majority of child tuberculosis (TB) deaths occur in children <5 years old, highlighting the importance of identifying young children at high risk of developing TB and initiating preventive treatment. However, current tests for Mycobacterium tuberculosis (Mtb) infection have poor predictive value for TB progression. To make progress toward biomarker-targeted TB preventive therapy in young children, there is an urgent need to identify novel host markers that reflect the unique pathogenesis of childhood TB, can be detected earlier in the course of disease progression and can be more easily translated to a point-of-care assay. The overall objective of the proposed project is to identify biomarker signatures among young children that meet the World Health Organization (WHO)-recommended minimum accuracy targets for a test of TB progression. We hypothesize that a subset of host biomarkers of childhood TB disease that reflect unsuccessful immune control of Mtb infection will have the best performance for early prediction of TB disease progression in young children. To examine our hypothesis, we propose to leverage 1) biorepositories that provide access to banked samples from children with presumptive TB and healthy children with and without TB exposure and Mtb infection (Uganda, South Africa, the Gambia); 2) biorepositories that provide serial samples from young children followed for 12 months or more for incident TB disease (Uganda, South Africa, Vietnam); and 3) state-of-the-art platforms and bioinformatic pipelines for multi-omics biomarker discovery. In Aim 1, we will measure and compare biomarker levels (host cell-free RNA, proteins, metabolites and antibodies to Mtb antigens) in symptomatic children with presumptive TB and healthy children to identify candidate host biomarkers that differentiate childhood TB disease, differentiate Mtb infection, overlap between TB disease and Mtb infection, and segregate Mtb infection into multiple sub-groups. In Aim 2, we will use pathway analysis, in vitro human models and in vivo mouse models to prioritize candidate host biomarkers that are functionally linked to immune control of Mtb infection. In Aim 3, we will derive biosignatures consisting of the prioritized candidate host biomarker(s) and evaluate their accuracy for predicting TB progression overall and among children living with HIV in independent training and test sets. Completion of these aims will result in identification of promising biosignatures that can be further validated in large-scale field studies and translated into point-of-care tests for predicting progression of childhood TB.