Metabolic biomarkers of TB disease, treatment response and infectiousness

项目3 -结核病的代谢生物标志物、治疗反应和传染性 项目负责人：Robin Wood 共同研究者：Kyu Rhee，Sara Suliman，迪格比Warner，D.分支穆迪 摘要 基于痰液的检测是现代结核病（TB）诊断的支柱，历史证明 无价之宝然而，其效用已被证明在临床环境和患者人群中是可变的， 疾病流行率和死亡率很高，包括儿童结核病和艾滋病毒合并感染的诊断 患者现有的诊断进一步主要集中在疾病检测上。然而，控制结核病 大流行最终还需要监测治疗效果和疾病传播能力。 项目3旨在通过开发一种新的基于代谢物的药物组合来解决这些未满足的诊断需求。 这些生物标志物存在于人血清和尿中，其容易从几乎所有受试者获得。我们 这种方法有可能实现实时监测治疗反应，诊断痰液， 阴性病例，并报告临床传染性。使用新的质谱分析平台， 以及从血清和尿液中进行无偏代谢物检测，我们发现了几种宿主代谢物 其水平使结核病的非侵入性诊断和治疗监测成为可能。一种代谢物的水平， 二乙酰精胺，用临床级ELISA检测，并发现与痰细菌 在独立的发现和验证队列中，在14天的治疗中的负荷和治疗反应。 展望未来，我们将沿着临床开发和使用的道路进一步验证这些分子 人血清和尿液的宽谱分析，以检测新的宿主和细菌代谢物 与结核病状态和治疗反应相关。我们会验证二乙酰精胺， 鞘磷脂和其他现有的主要候选代谢物在前瞻性队列中的临床效用 在化疗开始期间，结核病确诊和结核病阴性的结核病患者。我们将最终 测量结核病患者呼出的生物气溶胶中所含的活结核分枝杆菌，作为努力的生物基础 以鉴定和开发临床传染性的诊断生物标志物。我们打算验证新的测试 基于适合进入NIAID的现有血清和尿液生物标志物， 在当前TBRU期限内开展结核病诊断（FEND）计划。

Project 3 - Metabolic biomarkers of TB disease, treatment response and infectiousness Project Leader: Robin Wood Co-investigators: Kyu Rhee, Sara Suliman, Digby Warner, D. Branch Moody ABSTRACT Sputum-based tests are a mainstay of modern tuberculosis (TB) diagnostics that have historically proven invaluable. However, their utility has proven variable across clinical settings and patient populations where disease prevalence and mortality are high, including diagnosing TB in children and HIV co-infected patients. Existing diagnostics have further focused chiefly on disease detection. Yet, control of the TB pandemic ultimately also requires the ability to monitor treatment efficacy and disease transmissibility. Project 3 seeks to address these unmet diagnostic needs by developing a new panel of metabolite-based biomarkers present in human serum and urine, which are readily obtained from nearly all subjects. Our approach has the potential to enable real-time monitoring of treatment response, diagnose sputum- negative cases, and report on clinical infectiousness. Using new mass spectrometry platforms for broad and unbiased metabolite detection from serum and urine, we have discovered several host metabolites whose levels enabled non-invasive diagnosis and treatment monitoring of TB. Levels of one metabolite, diacetylspermine, were detectable with a clinical grade ELISA, and found to correlate with sputum bacterial load and treatment response over 14 days of therapy in independent discovery and validation cohorts. Going forward, we will validate these molecules further along the path to clinical development and use broad mass spectrometry profiling of human serum and urine to detect new host and bacterial metabolites associated with the TB disease state and treatment response. We will validate diacetylspermine, sphingomyelin and other existing lead candidate metabolites for their clinical utility in a prospective cohort of sputum-confirmed and sputum-negative TB patients during the initiation of chemotherapy. We will finally measure viable Mtb contained in exhaled bioaerosols of TB patients as the biological foundation of efforts to identify and develop diagnostic biomarkers of clinical infectiousness. We intend to validate new tests based on existing serum and urine biomarkers that are suitable for entry into the NIAID Feasibility of Novel Diagnostics for TB (FEND) program within the current TBRU term.