The DosR regulon of and adaptation to hypoxia.

Like other tuberculous and nontuberculous mycobacterial pathogens of human lung such as and , is likely exposed to a variety of stressors during infection, including hypoxic conditions inside activated macrophages and in the avascular necrotic regions of granulomas. How survives hypoxic stress to establish a chronic infection is currently not well understood. Using RNA-sequencing, we here show that grown under progressive microaerophilic conditions activates more than 4-fold a subset of 16 genes, the expression of 13 of which is dependent on the two-component system regulator DosRS. A subset of DosR regulon genes was confirmed to also be activated upon exposure to nitric oxide. Although a second sensor kinase besides DosS has been proposed to function with the transcriptional regulator DosR in , we show that this other kinase cannot compensate for a deficiency in DosS. Loss of expression in led to a significant reduction in viability under hypoxia that was more marked at acidic than at neutral pH. Unlike the situation in , however, loss of DosRS did not significantly impact the ability of to establish a drug tolerant state or form biofilms under host relevant conditions. Collectively, these results are suggestive of a lesser impact of DosRS on the ability of to develop antibiotic tolerance compared to other nontuberculous mycobacteria. The mutant further showed no signs of virulence attenuation in murine macrophages and in chronically infected immunocompetent BALB/c mice.