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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2021-09-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1009941 |
| _version_ | 1811314398618189824 |
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| author | Jeffrey M Collins Dean P Jones Ashish Sharma Manoj Khadka Ken H Liu Russell R Kempker Brendan Prideaux Kristal Maner-Smith Nestani Tukvadze N Sarita Shah James C M Brust Rafick-Pierre Sékaly Neel R Gandhi Henry M Blumberg Eric A Ortlund Thomas R Ziegler |
| author_facet | Jeffrey M Collins Dean P Jones Ashish Sharma Manoj Khadka Ken H Liu Russell R Kempker Brendan Prideaux Kristal Maner-Smith Nestani Tukvadze N Sarita Shah James C M Brust Rafick-Pierre Sékaly Neel R Gandhi Henry M Blumberg Eric A Ortlund Thomas R Ziegler |
| author_sort | Jeffrey M Collins |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T11:12:08Z |
| format | Article |
| id | doaj.art-5db2ee9eac9d436d93d78e7b9402b4da |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-04-13T11:12:08Z |
| publishDate | 2021-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-5db2ee9eac9d436d93d78e7b9402b4da2022-12-22T02:49:06ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742021-09-01179e100994110.1371/journal.ppat.1009941TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis.Jeffrey M CollinsDean P JonesAshish SharmaManoj KhadkaKen H LiuRussell R KempkerBrendan PrideauxKristal Maner-SmithNestani TukvadzeN Sarita ShahJames C M BrustRafick-Pierre SékalyNeel R GandhiHenry M BlumbergEric A OrtlundThomas R ZieglerThe 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.https://doi.org/10.1371/journal.ppat.1009941 |
| spellingShingle | Jeffrey M Collins Dean P Jones Ashish Sharma Manoj Khadka Ken H Liu Russell R Kempker Brendan Prideaux Kristal Maner-Smith Nestani Tukvadze N Sarita Shah James C M Brust Rafick-Pierre Sékaly Neel R Gandhi Henry M Blumberg Eric A Ortlund Thomas R Ziegler TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis. PLoS Pathogens |
| title | TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis. |
| title_full | TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis. |
| title_fullStr | TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis. |
| title_full_unstemmed | TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis. |
| title_short | TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis. |
| title_sort | tca cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis |
| url | https://doi.org/10.1371/journal.ppat.1009941 |
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