{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T21:32:09Z","timestamp":1768512729037,"version":"3.49.0"},"posted":{"date-parts":[[2024,6,11]]},"group-title":"Immunology","reference-count":53,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,6,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The natural diversity of\n                  <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                  is gaining relevance in dictating the outcome of tuberculosis (TB). We previously revealed a link between TB severity and\n                  <jats:italic>M. tuberculosis<\/jats:italic>\n                  -driven evasion of the macrophage cytosolic surveillance systems, with isolates from severe TB cases reducing inflammasome activation and interleukin (IL)-1\u03b2 production by infected cells. IL-1\u03b2 production and inflammasome activation are commonly associated with the metabolic reprogramming of stimulated macrophages. Thus, we questioned whether the differential modulation of the inflammasome and IL-1\u03b2 by\n                  <jats:italic>M. tuberculosis<\/jats:italic>\n                  isolates depended on distinct macrophage metabolic reprogramming. Using metabolic inhibitors, mice deficient for key metabolic regulators, and a metabolomics approach, we found that the macrophage metabolic landscape was similar regardless of the infecting\n                  <jats:italic>M. tuberculosis<\/jats:italic>\n                  isolate. Paralleling single-TLR activated macrophages, inhibition of glycolysis during infection impaired IL-1\u03b2 secretion. However, departing from TLR based models, in\n                  <jats:italic>M. tuberculosis<\/jats:italic>\n                  -infected macrophages IL-1\u03b2 secretion was independent of macrophage mitochondrial metabolic changes and the transcription factor hypoxia-inducible factor (HIF)-1\u03b1. Additionally, we found a previously unappreciated impact of host metabolic inhibitors on the pathogen, and show that inhibition of the mycobacteria metabolism dampened both inflammasome activation and IL-1\u03b2 production. Collectively, our study raises awareness of the potential confounding effect of host metabolic inhibitors acting on the pathogen itself and demonstrates that the modulation of the inflammasome by\n                  <jats:italic>M. tuberculosis<\/jats:italic>\n                  may be uncoupled from the host metabolic reprogramming.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Author Summary<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    is the causative agent of tuberculosis and one of the top infectious killers in the world, with around 1.3 million deaths reported annually. The genetic variability of this pathogen can shape its interaction with the host and modulate disease outcomes. We previously found that\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    clinical isolates from patients with severe forms of tuberculosis evade cytosolic surveillance systems in macrophages. Here, we explored whether this evasion tactic was linked to metabolic alterations in the infected macrophages. We found that different\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    isolates induced similar metabolic changes in infected macrophages. Additionally, we demonstrate that both host glycolysis and pathogen\u2019s metabolism were pivotal for maximum IL-1\u03b2 production. These findings highlight the complexity of macrophage-pathogen interactions and emphasize that bacterial metabolism should be considered in metabolic studies and may be amenable to therapeutic intervention against tuberculosis.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.06.10.598180","type":"posted-content","created":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T20:55:11Z","timestamp":1718139311000},"source":"Crossref","is-referenced-by-count":0,"title":["Genetically diverse Mycobacterium tuberculosis isolates manipulate inflammasome activation and IL-1\u03b2 secretion independently of macrophage metabolic rewiring"],"prefix":"10.64898","author":[{"given":"Ana Isabel","family":"Fernandes","sequence":"first","affiliation":[]},{"given":"Alexandre Jorge","family":"Pinto","sequence":"additional","affiliation":[]},{"given":"Diogo","family":"Silv\u00e9rio","sequence":"additional","affiliation":[]},{"given":"Ulrike","family":"Zedler","sequence":"additional","affiliation":[]},{"given":"Carolina","family":"Ferreira","sequence":"additional","affiliation":[]},{"given":"Iola F.","family":"Duarte","sequence":"additional","affiliation":[]},{"given":"Ricardo","family":"Silvestre","sequence":"additional","affiliation":[]},{"given":"Anca","family":"Dorhoi","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8180-1293","authenticated-orcid":false,"given":"Margarida","family":"Saraiva","sequence":"additional","affiliation":[]}],"member":"54368","reference":[{"key":"2024061501000940000_2024.06.10.598180v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.04.004"},{"key":"2024061501000940000_2024.06.10.598180v1.2","doi-asserted-by":"crossref","unstructured":"Diskin C , P\u00e5lsson-McDermott EM . 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