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TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis.

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.

SUBMITTER: Collins JM

PROVIDER: S-EPMC8494353 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis.

Collins Jeffrey M JM Jones Dean P DP Sharma Ashish A Khadka Manoj M Liu Ken H KH Kempker Russell R RR Prideaux Brendan B Maner-Smith Kristal K Tukvadze Nestani N Shah N Sarita NS Brust James C M JCM Sékaly Rafick-Pierre RP Gandhi Neel R NR Blumberg Henry M HM Ortlund Eric A EA Ziegler Thomas R TR

PLoS pathogens 20210924 9

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 de ...[more]

PMID: 34559866

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Dataset Information

TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis.

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TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis.

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