Central Metabolism Is Key Regulator of Macrophage Pyroptosis and Host Immunity.

Metabolic dysregulation in results in increased macrophage apoptosis or pyroptosis. However, mechanistic links between virulence and bacterial metabolic plasticity remain ill defined. In this study, we screened random transposon insertions of BCG to identify mutants that induce pyroptotic death of the infected macrophage. Analysis of the transposon insertion sites identified a panel of (unctioning eath epressor) genes, which were shown in some cases to encode functions central to metabolism. In-depth studies of one gene, (BCG3787/Rv3727), demonstrated its important role in the maintenance of and BCG redox balance in reductive stress conditions in the host. Our studies expand the subset of known genes linking bacterial metabolic plasticity to virulence and also reveal that the broad induction of pyroptosis by an intracellular bacterial pathogen is linked to enhanced cellular immunity in vivo.