Mycobacterium tuberculosis WhiB3 responds to vacuolar pH- induced changes in mycothiol redox potential to modulate phagosomal maturation and virulence [Microbiology]

December 4th, 2015 by Mehta, M., Rajmani, R. S., Singh, A.

The ability of Mycobacterium tuberculosis (Mtb) to resist intraphagosomal stresses such as oxygen radicals and low pH is critical for its persistence. Here, we show that a cytoplasmic redox sensor, WhiB3, and the major Mtb thiol, mycothiol (MSH), are required to resist acidic stress during infection. WhiB3 regulates the expression of genes involved in lipid anabolism, secretion, and redox metabolism, in response to acidic pH. Furthermore, inactivation of MSH pathway subverted the expression of whiB3 along with other pH-specific genes in Mtb. Using a genetic biosensor of mycothiol redox potential (EMSH), we demonstrated that a modest decrease in phagosomal pH is sufficient to generate redox heterogeneity in EMSH of the Mtb population in a WhiB3-dependent manner. Data indicate that Mtb needs low pH as a signal to alter cytoplasmic EMSH, which activates WhiB3-mediated gene expression and acid resistance. Importantly, WhiB3 regulates intraphagosomal pH by down-regulating the expression of innate immune genes and blocking phagosomal maturation. We show that this block in phagosomal maturation is in part due to WhiB3-dependant production of polyketide lipids. Consistent with these observations, MtbΔwhiB3 displayed intramacrophage survival defect, which can be rescued by pharmacological inhibition of phagosomal acidification. Lastly, MtbΔwhiB3 exhibited marked attenuation in the lungs of guinea pigs. Altogether, our study revealed an intimate link between vacuolar acidification, redox physiology, and virulence in Mtb, and discovered WhiB3 as crucial mediator of phagosomal maturation arrest and acid resistance in Mtb.
  • Posted in Journal of Biological Chemistry, Publications
  • Comments Off on Mycobacterium tuberculosis WhiB3 responds to vacuolar pH- induced changes in mycothiol redox potential to modulate phagosomal maturation and virulence [Microbiology]