A repressor co-regulatory network integrates iron acquisition to mycobacterial stress tolerance

Growing evidence suggests that controlled regulation of iron (Fe) uptake is essential for mycobacterial survival and proliferation in the host. In this study, we discovered the mechanism that links mycobacterial Fe acquisition to intra-bacterial redox environment via the phoP locus. Remarkably, regulated expression of the major Fe storage protein encoding gene bfrB determines bacterial tolerance to oxidative stress and intracellular survival of the pathogen. Transcriptomic analysis coupled with in vivo DNA binding studies uncover a distinct IdeR-independent regulation, which utilizes Lsr2 and virulence regulator PhoP to modulate transcriptional control of bfrB via recruitment of both the regulators. A striking inhibition of Lsr2 binding to the bfrB promoter in a phoP-KO mutant, attributable to Lsr2-PhoP protein-protein interaction, provides the most fundamental biological insight. Building on these results, we proposed a model suggesting how Lsr2-PhoP interaction (or lack thereof) contributes to repression and/or stress-specific activation of bfrB expression. Collectively, these results uncover a key mechanism linking Fe acquisition and oxidative stress response of mycobacteria, and have significant implications on the intracellular survival of the pathogen.