| Summary: | Metabolic dysregulation in <i>Mycobacterium tuberculosis</i> results in increased macrophage apoptosis or pyroptosis. However, mechanistic links between <i>Mycobacterium</i> virulence and bacterial metabolic plasticity remain ill defined. In this study, we screened random transposon insertions of <i>M. bovis</i> BCG to identify mutants that induce pyroptotic death of the infected macrophage. Analysis of the transposon insertion sites identified a panel of <i>fdr</i> (<i>f</i>unctioning <i>d</i>eath <i>r</i>epressor) genes, which were shown in some cases to encode functions central to <i>Mycobacterium</i> metabolism. In-depth studies of one <i>fdr</i> gene, <i>fdr8</i> (BCG3787/Rv3727), demonstrated its important role in the maintenance of <i>M. tuberculosis</i> and <i>M. bovis</i> BCG redox balance in reductive stress conditions in the host. Our studies expand the subset of known <i>Mycobacterium</i> 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.
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