Metabolic biomarkers of TB disease, treatment response and infectiousness

项目3--结核病的代谢生物标记物、治疗反应和传染性 项目负责人：罗宾·伍德 联合调查员：李京姬、萨拉·苏利曼、迪格比·华纳、D·布兰奇·穆迪 摘要 以痰为基础的检测是现代结核病诊断的支柱，历史证明 无价之宝。然而，它们的效用在临床环境和患者群体中已被证明是可变的 疾病流行率和死亡率都很高，包括诊断儿童结核病和艾滋病毒混合感染。 病人。现有的诊断进一步主要集中在疾病检测上。然而，结核病的控制 大流行最终还需要有能力监测治疗效果和疾病传播率。 项目3试图通过开发一种新的基于代谢物的小组来解决这些未得到满足的诊断需求 存在于人体血清和尿液中的生物标记物，几乎所有受试者都能轻易获得。我们的 该方法有可能实时监测治疗反应，诊断痰- 阴性病例，并报告临床传染性。使用新的质谱学平台进行广泛的 和从血清和尿液中无偏代谢物检测，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， 临床级别的酶联免疫吸附试验可检测到双乙酰精胺，并发现与痰细菌有关 独立发现和验证队列中超过14天的治疗负荷和治疗反应。 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 用于检测新宿主和细菌代谢物的人血清和尿液的广谱分析 与结核病的疾病状态和治疗反应有关。我们将验证双乙酰精胺， 神经鞘磷脂和其他现有主要候选代谢物在前瞻性队列中的临床应用 在开始化疗期间，对痰确诊和痰阴性的结核病患者进行监测。我们最终会 检测结核病患者呼出的生物气溶胶中的活结核分枝杆菌，作为努力的生物学基础 鉴定和开发临床感染性的诊断生物标志物。我们打算验证新的测试 基于现有的适合进入NIAID的血清和尿液生物标记物的可行性 当前TBRU期限内的结核病诊断(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.