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

确定儿童未来结核病进展风险的相关性 (INTREPID)

• 批准号: 10637036
• 负责人: James Alexander Seddon
• 金额: $ 84.09万
• 依托单位: STELLENBOSCH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-05 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10637036
• 关键词: 5 year old; Adult; Affect; Age; Antibodies; Antitubercular Agents; Bacille Calmette-Guerin vaccination; Bacillus; Bacteria; Bioinformatics; Biological; Biological Markers; Biology; Cessation of life; Child; Childhood; Classification; Clinical; Clinical Research; Collection; Cross-Sectional Studies; Cytomegalovirus; Data; Data Collection; Development; Diagnostic; Disease; Disease Progression; Drug resistance in tuberculosis; Epidemiology; Exposure to; Family; Future; Goals; HIV; HIV/TB; Health Services; Household; Immunologic Sensitization; Immunologics; Immunology; Immunology procedure; Individual; Infection; Longitudinal cohort; Mass Spectrum Analysis; Meningeal Tuberculosis; Metabolic; Methods; Morbidity - disease rate; Mycobacterium tuberculosis; Nested Case-Control Study; Nutritional status; Organism; Pathway Analysis; Pediatrics; Performance; Population; Positioning Attribute; Prevention; Preventive therapy; Proteomics; Recommendation; Research; Risk; Sampling; Scientist; Serology; South Africa; Subgroup; System; Testing; Therapy trial; Time; Toxic effect; Training; Tuberculosis; Viral; Virus; Virus Diseases; biomarker identification; biomarker signature; biosignature; clinical epidemiology; clinical translation; clinically relevant; co-infection; cohort; cost; design; disease classification; epidemiologic data; high risk; insight; metabolomics; mortality; novel marker; overtreatment; pathogen; pathogenic virus; predictive marker; predictive signature; prevent; progression risk; prospective; recruit; repository; response; transcriptomics; treatment response; tuberculosis treatment

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.

项目总结 背景：全球估计有7000万儿童感染结核分枝杆菌 (MTB)，引起结核病(TB)的细菌。在这些人中，每年有100万人患上结核病 其中四分之一的人会死。幼儿和艾滋病毒携带者感染结核分枝杆菌的风险很高。 导致结核病和发展成严重形式的结核病。因此，他们代表了一个关键的目标人群 结核病预防治疗(TPT)。向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，伴随着相关的费用和毒性。然而，目前对结核分枝杆菌的检测 感染不足以预测儿童疾病的未来发展。开发新的测试，准确地 预测哪些接触结核病的儿童将发展为结核病，这是一个关键的优先事项，并将使更有针对性 结核病预防的方法。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，包括年龄和接触其他常见病原体。已经显示了几种常见的病毒 影响患结核病的风险，并可能影响生物标记物的签名，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，免疫学上 对结核分枝杆菌而不是活杆菌敏感。如果有可能识别与结核分枝杆菌相关生物特征 在儿童死亡的情况下，这可能为幼儿采取有针对性的TPT方法提供另一种战略。我们的团队已经 儿科结核病转化性临床研究的广泛记录。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的三个严格进行的研究的样本&lt；5岁的一名耐药儿童。 结核病预防治疗试验、观察性家庭接触研究和前瞻性诊断研究，都是 在结核病和艾滋病毒负担较高的环境中进行。我们将进行横断面分析，以探索 纵向队列嵌套病例对照研究中结核病疾病谱生物特征的差异 评估发展为结核分枝杆菌感染和结核病的风险，以及评估签名变化的研究 关于结核分枝杆菌感染和早期疾病的治疗。我们将使用蛋白质组(SomaScan)、转录(RNA-seq)、 代谢组(质谱学)和抗体(系统血清学)方法，并使用训练/测试设计， 以确定生物标志物的特征。我们将在临床协变量和病毒的背景下检查生物签名 暴露(PepSeq和RNA-seq)。最后，我们将集成不同的方法来生成最健壮的 生物标记物组合，并提供对结核病疾病进展生物学的最细粒度的洞察。 影响：确定儿童结核病进展的新生物标记物，包括与 艾滋病毒，将改变全球对儿童结核病的反应。这将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。这将会有一个实质性的 对总体发病率和死亡率的影响。