Genetically Diverse <i>Mycobacterium tuberculosis</i> Isolates Manipulate Inflammasome and Interleukin 1β Secretion Independently of Macrophage Metabolic Rewiring

The diversity of Mycobacterium tuberculosis impacts the outcome of tuberculosis. We previously showed that M. tuberculosis isolates obtained from patients with severe disease induced low inflammasome activation and interleukin 1β (IL-1β) production by infected macrophages. Here we questioned whether this differential modulation of macrophages by M. tuberculosis isolates depended on distinct metabolic reprogramming. We found that the macrophage metabolic landscape was similar regardless of the infecting M. tuberculosis isolate. Paralleling single-Toll-like receptor (TLR) activated macrophages, glycolysis inhibition during infection impaired IL-1β secretion. However, departing from TLR -based models, in infected macrophages, IL-1β secretion was independent of mitochondrial metabolic changes and hypoxia-inducible factor 1α (HIF-1α). Additionally, we found an unappreciated impact of a host metabolic inhibitor on the pathogen, and show that inflammasome activation and IL-1β production by macrophages require metabolically active bacteria. Our study highlights the potential confounding effect of host metabolic inhibitors on the pathogen and uncoupling of M. tuberculosis-inflammasome modulation from the host metabolic reprogramming.