High-Resolution Plasma Metabolomic Profiling to Identify Biomarkers for Tuberculosis Disease and Response to Therapy

高分辨率血浆代谢组学分析可识别结核病生物标志物和治疗反应

• 批准号: 9432482
• 负责人: Dean Paul Jones
• 金额: $ 20.17万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-14 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9432482
• 关键词: Adult; Age; Amino Acids; Anti-Retroviral Agents; Antitubercular Agents; Applications Grants; Biological; Biological Markers; Blood; Caucasians; Cell Wall; Clinical Markers; Communicable Diseases; Country; Coupled; Data; Detection; Development; Diagnosis; Diagnostic tests; Diglycerides; Disease; Drug-sensitive; Functional disorder; Future; Glycolipids; Goals; HIV; HIV Seropositivity; Health; Household; Human; Hybrids; Individual; Ions; Knowledge; Lead; Link; Metabolic; Metabolic Pathway; Methods; Multidrug-Resistant Tuberculosis; Mycobacterium tuberculosis; Outcome; PIM1 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phosphatidylglycerols; Phosphatidylinositols; Pilot Projects; Plasma; Pulmonary Tuberculosis; Recovery; Recovery of Function; Regulation; Resolution; Sampling; Scheme; Sensitivity and Specificity; Series; South Africa; South African; Sputum; Testing; Time; Trehalose; Tuberculosis; Validation; attributable mortality; base; cell envelope; co-infection; cohort; design; disorder control; improved; lipid mediator; lipid metabolism; mass spectrometer; metabolic profile; metabolomics; mortality; mycolate; novel; pathogen; point-of-care diagnostics; potential biomarker; predictive marker; primary endpoint; rapid detection; response; secondary endpoint; sex; small molecule; specific biomarkers; treatment response; tuberculosis drugs; tuberculosis treatment; ultra high resolution

Summary/abstract: Tuberculosis (TB) is the number one infectious disease killer in the world with 1.5 million deaths attributable to the disease in 2014. A critical knowledge gap exists given the lack of biological pathways and predictive biomarkers related to TB onset, progression and resolution. An improved diagnostic test for TB would have a major impact on global control of the disease and reduce mortality. Unfortunately, there are no validated biomarkers for TB onset, progression and resolution; the development of a TB biomarker is urgently needed. Current ultra-high-resolution metabolomics (HRM) methods have considerable promise for the development of TB-associated biomarkers. Several studies have identified distinguishing small molecule metabolic profiles in blood and other bio samples in individuals with active Mycobacterium tuberculosis (Mtb)-induced TB disease compared to uninfected controls, but no studies have explored whether metabolomics is predictive of TB outcomes, Mtb clearance from sputum. Further, all studies to date have used low-resolution metabolomics methods. Advances in mass spectrometer machine capability, coupled with recent advanced data extraction/analysis methods has considerably increased the dynamic range of metabolite detection by HRM in biologic samples, which now exceeds 20,000 species (>100,000 ions). Our HRM processing scheme provides capability to detect very low abundance metabolites, including Mtb cell envelope glycolipids, and explore regulation of human metabolic pathways. In a pilot study, we successfully identified 61 plasma metabolites that differentiated adults with active pulmonary TB from household contacts without TB. Differentiating species included specific Mtb-derived cell wall glycolipids and endogenous lipid mediator resolvins. Our recent pilot data shows that specific metabolites and human metabolic pathways, including those involved in drug, amino acid, and lipid metabolism, are associated with the propensity for sputum Mtb culture clearance over time. The ultimate goal of this exploratory proposal is to obtain novel data that may lead to the development of new TB biomarkers. We hypothesize that plasma HRM analysis can: 1) predict the propensity for successful anti-TB treatment by identifying Mtb-derived and endogenous metabolites (biomarkers) and human metabolic pathways (pathophysiology) associated with sputum Mtb clearance; and 2) successfully differentiate patients with active TB from controls without latent TB infection (LTBI) or TB disease. To test these hypotheses, we propose the following Specific Aims in this exploratory R21 project: Specific Aim 1: To determine whether plasma HRM analysis can identify Mtb-derived and endogenous metabolites that predict clearance of Mtb from sputum (change from positive to negative culture). Specific Aim 2: To determine whether plasma HRM analysis can differentiate adults with drug- sensitive or MDR-TB ± HIV co-infection from asymptomatic controls without LTBI.

摘要/摘要：结核病 (TB) 是世界上第一大传染病杀手，有 150 万人罹患结核病 2014 年因该疾病死亡的人数。由于缺乏生物学知识，存在着严重的知识差距。 与结核病发病、进展和消退相关的途径和预测生物标志物。改进的诊断 结核病检测将对全球控制该疾病并降低死亡率产生重大影响。很遗憾， 对于结核病的发病、进展和消退，没有经过验证的生物标志物；结核病的发展 迫切需要生物标志物。当前的超高分辨率代谢组学（HRM）方法具有相当大的应用价值。 有望开发结核病相关生物标志物。几项研究已经确定了不同的小 活跃分枝杆菌个体血液和其他生物样本中的分子代谢特征 与未感染的对照相比，结核病 (Mtb) 诱发的结核病，但没有研究探讨是否 代谢组学可预测结核病结果以及痰中结核分枝杆菌的清除情况。此外，迄今为止的所有研究都使用 低分辨率代谢组学方法。质谱仪机器能力的进步，加上 最近先进的数据提取/分析方法大大增加了动态范围 通过 HRM 检测生物样品中的代谢物，目前生物样品中的代谢物超过 20,000 种（>100,000 个离子）。我们的 HRM 处理方案提供了检测极低丰度代谢物的能力，包括 Mtb 细胞 包膜糖脂，探索人体代谢途径的调节。在一项试点研究中，我们成功地 鉴定出 61 种血浆代谢物，可将患有活动性肺结核的成人与家庭接触者区分开来 无结核病。区分物种包括特定的结核分枝杆菌衍生的细胞壁糖脂和内源性脂质 调解员解决。我们最近的试点数据表明，特定的代谢物和人类代谢途径， 包括那些涉及药物、氨基酸和脂质代谢的物质，与以下倾向相关： 随着时间的推移，痰 Mtb 培养物会被清除。这个探索性提案的最终目标是获得新数据 这可能会导致新的结核病生物标志物的开发。我们假设血浆 HRM 分析可以：1) 通过识别结核分枝杆菌衍生的和内源性代谢物来预测成功抗结核治疗的倾向 与痰 Mtb 清除相关的（生物标志物）和人类代谢途径（病理生理学）；和 2) 成功区分活动性结核病患者与没有潜伏性结核病感染 (LTBI) 或结核病的对照患者。 为了检验这些假设，我们在这个探索性 R21 项目中提出以下具体目标： 具体目标 1：确定血浆 HRM 分析是否可以识别 Mtb 源性和内源性 预测痰液中 Mtb 清除率的代谢物（从阳性培养物变为阴性培养物）。 具体目标 2：确定血浆 HRM 分析是否可以区分成人药物- 来自无 LTBI 的无症状对照的敏感或 MDR-TB ± HIV 双重感染。