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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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/5db2ee9eac9d436d93d78e7b9402b4da
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spelling	oai:doaj.org-article:5db2ee9eac9d436d93d78e7b9402b4da2021-12-02T20:00:06ZTCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis.1553-73661553-737410.1371/journal.ppat.1009941https://doaj.org/article/5db2ee9eac9d436d93d78e7b9402b4da2021-09-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1009941https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374The 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.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 ZieglerPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 9, p e1009941 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 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.
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.
format	article
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
title	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_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_sort	tca cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/5db2ee9eac9d436d93d78e7b9402b4da
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TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis.

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