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（结核病）是世界上排名第一的感染疾病杀手 归因于该疾病在2014年的死亡。由于缺乏生物学而存在关键的知识差距 与结核病发作，进展和分辨率有关的途径和预测生物标志物。改进的诊断 结核病测试将对全球对疾病的控制并降低死亡率产生重大影响。很遗憾， 没有经过验证的结核病，进展和分辨率的生物标志物；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）方法已经考虑 有望发展与结核病相关的生物标志物。几项研究已经确定了较小的区别 活性分枝杆菌个体中血液和其他生物样品的分子代谢谱 与未感染的对照相比 代谢组学可预测结核病结果，痰液中的MTB清除率。此外，迄今为止使用的所有研究 低分辨率代谢组学方法。质谱仪机器能力的进步，并与 最近的高级数据提取/分析方法已清楚地增加了动态范围 HRM在生物样品中检测的代谢物检测，现在超过20,000种（> 100,000个离子）。我们的 HRM处理方案提供了检测非常低丰度代谢物的功能，包括MTB单元 包膜糖胶质，并探索人类代谢途径的调节。在一项试点研究中，我们成功地 确定了61个血浆代谢产物，这些代谢物用活跃的肺结核与家庭接触区分了活性的成年人 没有结核病。区分物种包括特定的MTB衍生的细胞壁糖脂和内源性脂质 调解器分辨率。我们最近的试验数据表明，特定的代谢产物和人类代谢途径， 包括参与药物，氨基酸和脂质代谢的人，与对 随着时间的流逝，痰MTB培养清除。该探索性建议的最终目标是获取新的数据 这可能会导致新的结核病生物标志物的发展。我们假设血浆HRM分析可以：1） 通过鉴定MTB衍生和内源性代谢物，预测成功抗TB治疗的希望 （生物标志物）和与痰MTB清除相关的人类代谢途径（病理生理）；和2） 成功地将活性结核病患者与没有潜在结核病感染（LTBI）或结核病疾病的对照区分开。 为了检验这些假设，我们在此探索性R21项目中提出了以下具体目标： 特定目的1：确定血浆HRM分析是否可以识别MTB衍生和内源性 预测痰中MTB清除的代谢产物（从阳性变为负培养）。 具体目标2：确定血浆HRM分析是否可以使成年人与药物区分开 没有LTBI的不对称控制的敏感或MDR-TB±HIV共感染。