Frediani Jennifer K, Jones Dean P, Tukvadze Nestan, Uppal Karan, Sanikidze Eka, Kipiani Maia, Tran ViLinh T, Hebbar Gautam, Walker Douglas I, Kempker Russell R, Kurani Shaheen S, Colas Romain A, Dalli Jesmond, Tangpricha Vin, Serhan Charles N, Blumberg Henry M, Ziegler Thomas R
Nutrition and Health Sciences, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University, Atlanta, Georgia, United States of America; Center for Clinical and Molecular Nutrition, Emory University School of Medicine, Atlanta, Georgia, United States of America; Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
National Center for Tuberculosis and Lung Disease, Tbilisi, Georgia.
PLoS One. 2014 Oct 15;9(10):e108854. doi: 10.1371/journal.pone.0108854. eCollection 2014.
We aimed to characterize metabolites during tuberculosis (TB) disease and identify new pathophysiologic pathways involved in infection as well as biomarkers of TB onset, progression and resolution. Such data may inform development of new anti-tuberculosis drugs. Plasma samples from adults with newly diagnosed pulmonary TB disease and their matched, asymptomatic, sputum culture-negative household contacts were analyzed using liquid chromatography high-resolution mass spectrometry (LC-MS) to identify metabolites. Statistical and bioinformatics methods were used to select accurate mass/charge (m/z) ions that were significantly different between the two groups at a false discovery rate (FDR) of q<0.05. Two-way hierarchical cluster analysis (HCA) was used to identify clusters of ions contributing to separation of cases and controls, and metabolomics databases were used to match these ions to known metabolites. Identity of specific D-series resolvins, glutamate and Mycobacterium tuberculosis (Mtb)-derived trehalose-6-mycolate was confirmed using LC-MS/MS analysis. Over 23,000 metabolites were detected in untargeted metabolomic analysis and 61 metabolites were significantly different between the two groups. HCA revealed 8 metabolite clusters containing metabolites largely upregulated in patients with TB disease, including anti-TB drugs, glutamate, choline derivatives, Mycobacterium tuberculosis-derived cell wall glycolipids (trehalose-6-mycolate and phosphatidylinositol) and pro-resolving lipid mediators of inflammation, known to stimulate resolution, efferocytosis and microbial killing. The resolvins were confirmed to be RvD1, aspirin-triggered RvD1, and RvD2. This study shows that high-resolution metabolomic analysis can differentiate patients with active TB disease from their asymptomatic household contacts. Specific metabolites upregulated in the plasma of patients with active TB disease, including Mtb-derived glycolipids and resolvins, have potential as biomarkers and may reveal pathways involved in TB disease pathogenesis and resolution.
我们旨在表征结核病（TB）病程中的代谢物，识别参与感染的新病理生理途径以及结核病发病、进展和缓解的生物标志物。此类数据可能为新型抗结核药物的研发提供信息。使用液相色谱高分辨率质谱（LC-MS）分析新诊断为肺结核病的成年人及其匹配的无症状、痰培养阴性的家庭接触者的血浆样本，以识别代谢物。采用统计和生物信息学方法，以错误发现率（FDR）q<0.05选择两组之间存在显著差异的精确质量/电荷（m/z）离子。使用双向层次聚类分析（HCA）识别有助于区分病例组和对照组的离子簇，并使用代谢组学数据库将这些离子与已知代谢物进行匹配。使用LC-MS/MS分析确认了特定D系列消退素、谷氨酸和结核分枝杆菌（Mtb）衍生的海藻糖-6-分枝菌酸的身份。在非靶向代谢组学分析中检测到超过23000种代谢物，两组之间有61种代谢物存在显著差异。HCA揭示了8个代谢物簇，其中包含在结核病患者中大量上调的代谢物，包括抗结核药物、谷氨酸、胆碱衍生物、结核分枝杆菌衍生的细胞壁糖脂（海藻糖-6-分枝菌酸和磷脂酰肌醇）以及已知可刺激炎症消退、胞葬作用和微生物杀灭的促消退脂质介质。确认消退素为RvD1、阿司匹林触发的RvD1和RvD2。这项研究表明，高分辨率代谢组学分析可以区分活动性结核病患者与其无症状的家庭接触者。活动性结核病患者血浆中上调的特定代谢物，包括Mtb衍生的糖脂和消退素，有潜力作为生物标志物，并可能揭示参与结核病发病机制和消退的途径。
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