Identifying correlates of risk for future tuberculosis disease progression in children (INTREPID)

项目摘要 背景：据估计，全球有7000万儿童感染结核分枝杆菌 (Mtb)结核病是由结核杆菌引起的。其中，每年有100万人患上结核病， 四分之一的人死亡。幼儿和艾滋病毒感染者感染结核分枝杆菌的风险很高 结核病和发展成严重形式的结核病。因此，他们是一个关键的目标群体 结核病预防治疗（TPT）。为所有接触结核病的儿童提供TPT，特别是在结核病高发地区 负担，导致大量的过度治疗，伴随着相关的成本和毒性。然而，目前的结核病测试 感染不足以预测儿童疾病未来进展。开发新的测试， 预测哪些结核病暴露儿童将发展为结核病，是一个关键的优先事项，将允许更有针对性的 预防结核病的方法。儿童结核分枝杆菌生物标志物的鉴定还应考虑其他相关因素。 因素，包括年龄和暴露于其他常见病原体。几种常见的病毒 影响患结核病的风险，并可能影响生物标志物，但很少有研究评估 病毒对儿童结核病生物标志物的影响。最后，目前对结核分枝杆菌感染的检测表明， 对结核分枝杆菌而不是活杆菌敏感。如果有可能识别出与结核分枝杆菌相关的生物特征 死亡，这可以提供一个额外的战略，有针对性的TPT方法在幼儿。我们集团 儿科结核病转化临床研究的广泛跟踪记录。我们的团队由世界领导人组成 在临床儿科学、流行病学、免疫学、蛋白质组学、转录组学和生物信息学领域。 方法：我们将使用来自我们在5岁以下儿童中进行的三项严格研究的样本， 结核病预防性治疗试验、观察性家庭接触研究和前瞻性诊断研究， 在结核病和艾滋病毒高负担的环境中进行。我们将进行横向分析， 沿着结核病谱的生物特征差异，纵向队列的嵌套病例对照研究 评估进展为结核分枝杆菌感染和结核病的风险，以及评估特征变化的研究 结核病感染和早期疾病的治疗。我们将使用蛋白质组学（SomaScan），转录组学（RNA-seq）， 代谢组学（质谱）和抗体（系统血清学）方法，并使用训练/测试设计， 来识别生物标记物。我们将在临床协变量和病毒背景下检查生物特征 暴露（PepSeq和RNA-seq）。最后，我们将整合不同的方法，以生成最强大的 生物标志物组合，并提供对结核病进展的生物学的最细粒度的见解。 影响：确定幼儿结核病进展的新生物标志物，包括那些患有结核病的儿童 艾滋病毒，将改变全球对儿童结核病的反应。这是第一次有可能预防结核病 通过识别和有效治疗未来疾病风险最高的儿童。这将是一个巨大的 对总体发病率和死亡率的影响。

PROJECT SUMMARY Background: Seventy million children globally are estimated to be infected with Mycobacterium tuberculosis (Mtb), the bacteria which causes tuberculosis (TB). Of these, 1 million develop TB disease each year with a quarter of them dying. Young children and those living with HIV are at high risk of progressing from Mtb infection to TB disease and of developing severe forms of TB. They therefore represent a key population to target with TB preventive therapy (TPT). Providing TPT to all children exposed to TB, especially in settings with high TB burden, results in substantial overtreatment, with associated costs and toxicity. Yet the current tests of Mtb infection are inadequate to predict future progression to disease in children. Developing new tests that accurately predict which TB-exposed children will progress to TB, is a critical priority and will allow for more targeted approaches to TB prevention. The identification of Mtb biomarkers in children should also consider relevant other factors, including age, and exposure to other common pathogens. Several common viruses have been shown to influence the risk of developing TB and are likely to affect biomarker signatures, yet few studies have evaluated the influence of viruses on childhood TB biomarkers. Finally, current tests of Mtb infection indicate immunological sensitization to Mtb rather than viable bacilli. If it were possible to identify a biosignature associated with Mtb death, this could provide an additional strategy for targeted TPT approaches in young children. Our group has an extensive track record of translational clinical research into pediatric TB. Our team consists of world leaders in the fields of clinical pediatrics, epidemiology, immunology, proteomics, transcriptomics, and bioinformatics. Methods: We will use samples from our three rigorously conducted studies in children <5 years, a drug-resistant TB preventive therapy trial, an observational household contact study, and a prospective diagnostic study, all conducted in a setting with high burden of TB and HIV. We will carry out a cross-sectional analysis to explore differences in biosignatures along the TB disease spectrum, nested case-control studies in longitudinal cohorts to evaluate risks of progression to Mtb infection and TB disease, and studies to evaluate changes in signatures on treatment for Mtb infection and early disease. We will use proteomic (SomaScan), transcriptomic (RNA-seq), metabolomic (mass spectrometry) and antibody (Systems Serology) approaches, and use a training/test design, to identify biomarker signatures. We will examine biosignatures in the context of clinical co-variates and viral exposure (PepSeq and RNA-seq). Finally, we will integrate the different approaches to generate the most robust biomarker combinations and provide the most granular insight into the biology of TB disease progression. Impact: Identifying novel biomarkers of TB disease progression in young children, including those living with HIV, would transform the global response to pediatric TB. For the first time, it would be possible to prevent TB by identifying and effectively treating children at the highest risk of future disease. This would have a substantial impact on overall morbidity and mortality.