TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis

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...

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Veröffentlicht in:PLoS pathogens Jg. 17; H. 9; S. e1009941
Hauptverfasser: Collins, Jeffrey M., Jones, Dean P., Sharma, Ashish, Khadka, Manoj, Liu, Ken H., Kempker, Russell R., Prideaux, Brendan, Maner-Smith, Kristal, Tukvadze, Nestani, Shah, N. Sarita, Brust, James C. M., Sékaly, Rafick-Pierre, Gandhi, Neel R., Blumberg, Henry M., Ortlund, Eric A., Ziegler, Thomas R.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: San Francisco Public Library of Science 24.09.2021
Public Library of Science (PLoS)
Schlagworte:
Accumulation
Arachidonic acid
Asymptomatic
Biology and Life Sciences
Carboxylic acids
Cellular signal transduction
Chemotherapy
Chromatography
Correlation analysis
COVID-19
Cytokines
Dehydrogenases
Development and progression
Drug therapy
Eicosanoids
Fatty acids
Health aspects
HIV
Human immunodeficiency virus
IL-1β
Infections
Inflammation
Intermediates
Lipids
Lung diseases
Medicine and Health Sciences
Metabolic response
Metabolism
Metabolites
Metabolomics
Multidrug resistance
Phospholipase A2
Physiological aspects
Plasma
Pulmonary tuberculosis
Signaling
Tricarboxylic acid cycle
Tuberculosis
United States
ISSN:1553-7374, 1553-7366, 1553-7374
Online-Zugang:Volltext
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Zusammenfassung: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.
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These authors are co-senior authors on this work.
The authors have declared that no competing interests exist.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1009941