TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis

• DOI: 10.1371/journal.ppat.1009941
• Publication Date: 2021-09-24T18:03:33Z
• Authors: 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
• Keywords: Proinflammatory cytokine; Metabolic pathway

The metabolic signaling pathways that drive pathologic tissue inflammation and damage in humans with pulmonary tuberculosis (TB) are not well understood. Using combined methods plasma high-resolution metabolomics, lipidomics cytokine profiling from a multicohort study of TB disease, we discovered IL-1β-mediated inflammatory was closely associated TCA cycle remodeling, characterized by accumulation the proinflammatory metabolite succinate decreased concentrations anti-inflammatory itaconate. This response particularly active persons multidrug-resistant (MDR)-TB received at least 2 months ineffective treatment only reversed after 1 year appropriate anti-TB chemotherapy. Both IL-1β were significantly lipid signaling, including increases products phospholipase A2, increased arachidonic acid formation, metabolism to eicosanoids. Together, these results indicate itaconate other intermediates is eicosanoid disease. These findings support host remodeling as key driver human