Plasma Metabolomics in Human Pulmonary Tuberculosis Disease: A Pilot Study

• Type of Material: Article
• Authors: Jennifer K. Frediani, Emory University; Dean P Jones, Emory University; Nestan Tukvadze, National Center for Tuberculosis and Lung Disease; Karan Uppal, Emory University; Eka Sanikidze, National Center for Tuberculosis and Lung Disease; Maia Kipiani, National Center for Tuberculosis and Lung Disease; ViLinh T. Tran, Emory University; Gautam Hebbar, Emory University; Douglas Walker, Emory University; Russell Kempker, Emory University; Shaheen S. Kurani, Emory University; Romain A. Colas, Harvard Medical School; Jesmond Dalli, Harvard Medical School; Vin Tangpricha, Emory University; Charles N. Serhan, Harvard Medical School; Henry Michael Blumberg, Emory University; Thomas Ziegler, Emory University
• Language: English
• Date: 2014-10-15
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: ©2014 Frediani et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pone.0108854
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 9
• Issue: 10
• Start Page: e108854
• End Page: e108854
• Grant/Funding Information: This work was supported in part by National Institutes of Health (www.nih.gov)grants UL1 TR000454 (Atlanta Clinical and Translational Science Institute www.actsi.org), K24 DK096574 (TRZ), R01 ES016731, P30ES019776, HHSN272201200031C, P20HL113451 and R01 AG038746 (DPJ), D43 TW007124 (HMB), P01 GM095467 (CNS, JD, RAC), K23 AR054334 (VT), K23 AI103044 (RRK) and the Emory University Global Health Institute (http://www.globalhealth.emory.edu/) (TRZ, VT, HMB).; The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• Keywords: IDENTIFICATION; HOST; Science & Technology - Other Topics; HUMAN PHAGOCYTES; RESOLVINS; RESOLUTION; Multidisciplinary Sciences; TRICARBOXYLIC-ACID CYCLE; LIPID MEDIATORS; METABOLISM; Science & Technology; CELL-WALL; MYCOBACTERIUM-TUBERCULOSIS
• Research Categories: Health Sciences, Public Health; Health Sciences, Epidemiology

Abstract

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. Copyright: