Two Sensor Kinases Contribute to the Hypoxic Response of Mycobacterium tuberculosis

Current estimates indicate that nearly a third of the world's population is latently infected with Mycobacterium tuberculosis. Reduced oxygen tension and nitric oxide exposure are two conditions encountered by bacilli in vivo that may promote latency. In vitro exposure to hypoxia or nitric oxide results in bacterial stasis with concomitant induction of a 47-gene regulon controlled by the transcription factor DosR. In this report we demonstrate that both the dosS gene adjacent to dosR and another gene, dosT (Rv2027c), encode sensor kinases, each of which can autophosphorylate at a conserved histidine and then transfer phosphate to an aspartate residue of DosR. Mutant bacteria lacking both sensors are unable to activate expression of DosR-regulated genes. These data indicate that DosR/DosS/DosT comprise a two-component signaling system that is required for the M. tuberculosis genetic response to hypoxia and nitric oxide, two conditions that produce reversible growth arrest in vitro and may contribute to latency in vivo.