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.

项目摘要 背景：估计全球700万儿童感染了结核分枝杆菌 （MTB），导致结核病（TB）的细菌。其中，每年有100万人患有结核病疾病 他们的四分之一死了。幼儿和艾滋病毒感染者的高风险从MTB感染中 结核病疾病和发展严重的结核病形式。因此，它们代表着一个关键人群，以 结核病预防疗法（TPT）。为暴露于结核病的所有儿童提供TPT，尤其是在TB高的情况下 负担，导致过度治疗，相关成本和毒性。然而当前的MTB测试 感染不足以预测儿童的未来进展。开发准确的新测试 预测哪些暴露于结核病的儿童将发展为结核病，这是一个关键的优先事项，将允许更有针对性 预防结核病的方法。儿童中MTB生物标志物的识别也应考虑其他相关的其他 因素，包括年龄和暴露于其他常见病原体。已经显示了几种常见病毒 影响开发结核病的风险并可能影响生物标志物的特征，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，MTB感染的当前测试表明免疫学 对MTB而不是可行的细菌的敏化。如果可以识别与MTB相关的生物签名 死亡，这可以为幼儿的针对性TPT方法提供额外的策略。我们的小组有 转化临床研究对小儿结核病的广泛记录。我们的团队由世界领导人组成 在临床儿科，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：我们将使用三个严格进行的研究中的样本在<5岁的儿童中，一种耐药性 结核病预防疗法试验，一项观察性家庭接触研究和一项前瞻性诊断研究 在TB和HIV负担很高的环境中进行。我们将进行横截面分析以探索 沿TB疾病谱系的生物签名差异，纵向人群中嵌套的病例对照研究 评估进展为MTB感染和结核病疾病的风险，以及评估签名变化的研究 关于MTB感染和早期疾病的治疗。我们将使用蛋白质组学（Somascan），转录组（RNA-Seq）， 代谢组学（质谱法）和抗体（系统血清学）方法，并使用训练/测试设计， 识别生物标志物签名。我们将在临床共同变化和病毒的背景下检查生物签名 暴露（Pepseq和RNA-Seq）。最后，我们将整合不同的方法来生成最健壮的方法 生物标志物组合，并对结核病疾病进展的生物学提供最细致的见解。 影响：识别幼儿中结核病疾病进展的新型生物标志物，包括患有的孩子 艾滋病毒将改变全球对小儿结核病的反应。首次可以防止结核病 通过识别并有效治疗未来疾病风险最高的儿童。这将有很大的 对整体发病率和死亡率的影响。