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.

Immune evasion and provocation by Mycobacterium tuberculosis

“…Although IL-1β is host-protective during early stages of TB, as the disease progresses, it can enhance pro-inflammatory eicosanoid production, resulting in an influx of neutrophils and exacerbating tissue pathology 58 , 59 . In the case of human pulmonary TB, a recent study of patients with untreated multidrug-resistant M. tuberculosis found that IL-1β and pro-inflammatory eicosanoids correlated with tricarboxylic acid cycle remodelling 60 . Mitochondria are central to host immunometabolism as they house multiple metabolic pathways, impact cell death and inflammasome activation, and produce ROS 61 .…”

Jingfang Granule Protects Against Concanavalin-A-Induced Immune Hepatitis in Mice Through Regulating Tricarboxylic Acid Cycle

“…Unusual activity of TCA cycle intermediates leads to the activation of in ammatory cells, which in turn leads to the up-regulation of proin ammatory factors [17,62]. There is evidence that the remodeling of TCA cycle is related to the secretion of pro-in ammatory IL-1β and the signal transduction of IFN-γ, while IL-1β and IFN-γ are pro-in ammatory cytokines that mediate different kinds of immune responses [73].…”

“…6D). TCA circulation pathway give scope to remarkable affect in mediating in ammatory response, and its effect on body function by regulating in ammation has been con rmed by many studies [33][34][35][36][37].…”

Drug resistant tuberculosis: Implications for transmission, diagnosis, and disease management

“…This effect is not seen with drug susceptible TB. While inflammatory signalling and TCA cycle remodelling occurs during drug susceptible TB infection, 2 months of ineffective treatment of MDR-TB resulted in a marked upregulation of this inflammatory cascade, an effect that took a year to reverse (Collins et al, 2021). These, and related effects, should be carefully investigated to develop appropriate health systems strategies for monitoring outcomes of drug resistant TB.…”