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
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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.
AbstractList	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-1[beta]-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-1[beta] 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-1[beta]-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. 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. 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.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. 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. Pulmonary tuberculosis (TB) often results in pathologic lung inflammation that causes tissue damage and does not control bacterial replication. This impairs the host response to antibiotic treatment and can result in long term deficits in lung function. Currently, the role of host metabolism in regulating the inflammatory response in TB disease is not well understood. Here, we use detailed immunometabolic phenotyping to show that metabolic remodeling of the tricarboxylic acid (TCA) cycle is closely associated with pathologic inflammatory signaling in humans with TB disease. Accumulation of TCA cycle intermediates in plasma, including the proinflammatory metabolite succinate, as well as decreased concentrations of the anti-inflammatory metabolite itaconate, were associated with increases in IL-1β and upregulation of proinflammatory lipid signaling cascades. This inflammatory network was upregulated following delays in appropriate anti-TB treatment and was associated with prolonged time to sputum culture clearance of Mycobacterium tuberculosis. Our study provides new insights into the metabolic reprograming that leads to pathologic inflammation in humans with pulmonary TB.
Audience	Academic
Author	Khadka, Manoj Kempker, Russell R. Collins, Jeffrey M. Maner-Smith, Kristal Sékaly, Rafick-Pierre Prideaux, Brendan Blumberg, Henry M. Jones, Dean P. Brust, James C. M. Ziegler, Thomas R. Shah, N. Sarita Ortlund, Eric A. Liu, Ken H. Tukvadze, Nestani Sharma, Ashish Gandhi, Neel R.
AuthorAffiliation	5 National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia 9 Section of Endocrinology, Atlanta Veterans Affairs Medical Center, Atlanta, Georgia, United States of America 4 Department of Neuroscience, Cell Biology, & Anatomy, University of Texas Medical Branch, Galveston, Texas, United States of America Portland VA Medical Center, Oregon Health and Science University, UNITED STATES 7 Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, Georgia, United States of America 1 Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America 6 Department of Global Health, Emory University Rollins School of Public Health, Atlanta, Georgia, United States of America 3 Department of Biochemistry, Emory University, Atlanta, Georgia, United States of America 2 Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, United States of America 8 Department of Medicine, Albert Einstein College of Medicine
AuthorAffiliation_xml	– name: 4 Department of Neuroscience, Cell Biology, & Anatomy, University of Texas Medical Branch, Galveston, Texas, United States of America – name: 1 Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America – name: 2 Department of Pathology, Emory University School of Medicine, Atlanta, Georgia, United States of America – name: Portland VA Medical Center, Oregon Health and Science University, UNITED STATES – name: 3 Department of Biochemistry, Emory University, Atlanta, Georgia, United States of America – name: 6 Department of Global Health, Emory University Rollins School of Public Health, Atlanta, Georgia, United States of America – name: 8 Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, United States of America – name: 5 National Center for Tuberculosis and Lung Diseases, Tbilisi, Georgia – name: 7 Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, Georgia, United States of America – name: 9 Section of Endocrinology, Atlanta Veterans Affairs Medical Center, Atlanta, Georgia, United States of America
Author_xml	– sequence: 1 givenname: Jeffrey M. orcidid: 0000-0002-6574-0873 surname: Collins fullname: Collins, Jeffrey M. – sequence: 2 givenname: Dean P. orcidid: 0000-0002-2090-0677 surname: Jones fullname: Jones, Dean P. – sequence: 3 givenname: Ashish surname: Sharma fullname: Sharma, Ashish – sequence: 4 givenname: Manoj orcidid: 0000-0002-4003-7049 surname: Khadka fullname: Khadka, Manoj – sequence: 5 givenname: Ken H. orcidid: 0000-0002-9736-5828 surname: Liu fullname: Liu, Ken H. – sequence: 6 givenname: Russell R. orcidid: 0000-0002-7188-4996 surname: Kempker fullname: Kempker, Russell R. – sequence: 7 givenname: Brendan surname: Prideaux fullname: Prideaux, Brendan – sequence: 8 givenname: Kristal orcidid: 0000-0002-2274-4284 surname: Maner-Smith fullname: Maner-Smith, Kristal – sequence: 9 givenname: Nestani surname: Tukvadze fullname: Tukvadze, Nestani – sequence: 10 givenname: N. Sarita surname: Shah fullname: Shah, N. Sarita – sequence: 11 givenname: James C. M. orcidid: 0000-0003-3362-1818 surname: Brust fullname: Brust, James C. M. – sequence: 12 givenname: Rafick-Pierre surname: Sékaly fullname: Sékaly, Rafick-Pierre – sequence: 13 givenname: Neel R. surname: Gandhi fullname: Gandhi, Neel R. – sequence: 14 givenname: Henry M. orcidid: 0000-0002-3110-2443 surname: Blumberg fullname: Blumberg, Henry M. – sequence: 15 givenname: Eric A. orcidid: 0000-0001-8855-3029 surname: Ortlund fullname: Ortlund, Eric A. – sequence: 16 givenname: Thomas R. surname: Ziegler fullname: Ziegler, Thomas R.
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Copyright	COPYRIGHT 2021 Public Library of Science 2021 Collins et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. 2021 Collins et al 2021 Collins et al
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Snippet	The metabolic signaling pathways that drive pathologic tissue inflammation and damage in humans with pulmonary tuberculosis (TB) are not well understood. Using...
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SubjectTerms	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
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Title	TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis
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