부산대학교 도서관

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. Author summary: 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. [ABSTRACT FROM AUTHOR]