TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis

• Type of Material: Article
• Authors: Jeffrey Collins, Emory University; Dean Jones, Emory University; Ashish Sharma, Emory University; Manoj Khadka, Emory University; Ken Liu, Emory University; Russell Kempker, Emory University; Brendan Prideaux, University of Texas Medical Branch; Kristal Maner-Smith, Emory University; Nestani Tukvadze, National Center for Tuberculosis and Lung Diseases; N. Sarita Shah, Emory University; James C. M. Brust, Albert Einstein College of Medicine; Rafick-Pierre Sekaly, Emory University; Neel Gandhi, Emory University; Henry Blumberg, Emory University; Eric Ortlund, Emory University; Thomas Ziegler, Emory University
• Language: English
• Date: 2021-09-01
• Publisher: PUBLIC LIBRARY SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Collins et al
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1009941
• Title of Journal or Parent Work: PLOS PATHOGENS
• Volume: 17
• Issue: 9
• Start Page: e1009941
• End Page: e1009941
• Grant/Funding Information: The study has received funding from: National Institutes of Health grant R21 AI130918 (TRZ, NRG, JCMB, DPJ, RRK, HMB) National Institutes of Health grant K23 AI144040 (JMC) National Institutes of Health grant P30 AI050409 (JMC) National Institutes of Health grant T32 AI074492 (JMC) National Institutes of Health grant P30 ES019776 (DPJ, TRZ) National Institutes of Health grant R01 AI087465 (NRG, NSS, JCMB) National Institutes of Health grant K24 AI114444 (NRG) National Institutes of Health grant D43 TW007124 (RRK, HMB) National Institutes of Health grant R01AI114304 (JCMB) National Institutes of Health grant R01AI145679 (JCMB) National Institutes of Health grant K24AI155045 (JCMB) National Institutes of Health grant P30AI124414 (JCMB) National Institutes of Health grant UL1 TR002378 (JMC, MK, HMB, EAO, TRZ) National Institutes of Health grant UL1TR001073 (JCMB) Emory University Global Health Institute (TRZ, HMB, NT, RRK) Emory Medical Care Foundation (RRK, JMC, HMB, TRZ) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• Keywords: BIOMARKERS; SUCCINATE-DEHYDROGENASE; IL-1-BETA; MASS-SPECTROMETRY; Virology; METABOLITE; Parasitology; Life Sciences & Biomedicine; Microbiology; MULTIDRUG-RESISTANT TUBERCULOSIS; METABOLOMICS; ITACONATE; Science & Technology
• Research Categories: Biology, Virology; Biology, Parasitology

Abstract

The metabolic signaling pathways that drive pathologic tissue inflammation and damage in humans with pulmonary tuberculosis (TB) are not well understood. Using combined methods in plasma high-resolution metabolomics, lipidomics and cytokine profiling from a multicohort study of humans with pulmonary TB disease, we discovered that IL-1β-mediated inflammatory signaling was closely associated with TCA cycle remodeling, characterized by accumulation of the proinflammatory metabolite succinate and decreased concentrations of the anti-inflammatory metabolite itaconate. This inflammatory metabolic response was particularly active in persons with multidrug-resistant (MDR)-TB that received at least 2 months of ineffective treatment and was only reversed after 1 year of appropriate anti-TB chemotherapy. Both succinate and IL-1β were significantly associated with proinflammatory lipid signaling, including increases in the products of phospholipase A2, increased arachidonic acid formation, and metabolism of arachidonic acid to proinflammatory eicosanoids. Together, these results indicate that decreased itaconate and accumulation of succinate and other TCA cycle intermediates is associated with IL-1β-mediated proinflammatory eicosanoid signaling in pulmonary TB disease. These findings support host metabolic remodeling as a key driver of pathologic inflammation in human TB disease.