NO, CO, and O2 sensing by the Mtb Dos dormancy three-component system. Schematic representation of the Mtb heme sensor kinases DosS (A) and DosT (B) that are responsive to the in vivo gas ligands NO, CO, and O2. (A) One model proposes that DosS is in the inactive state when ferrous heme iron is oxidized by environmental O2 to produce met (Fe3+) heme. The autokinase activity of DosS is activated when met heme is reduced by a cellular redox couple (e.g., FdxA, chorismate synthase, vitamin C). Another model proposes that DosS is in the oxy (“off”) state and is activated by loss of O2 (e.g., during hypoxia) to generate ferrous DosS. When NO or CO (host gases produced by iNOS and HO-1, respectively) are the ligands, NO-DosS and CO-DosS are generated, which keep DosS in a “locked”, activated state. Because of the stability of the gas complexes, DosS (and DosT) is provided with an additional level of regulation. (B) DosT is proposed to be in an inactive Fe-O2 form. During hypoxic conditions, bound O2 is released from DosT, leading to the formation of active, ferrous DosT. Again, NO and CO can keep DosT in a “locked” state by generating CO-DosT or NO-DosT. The active forms of DosS and DosT in turn activate the Dos regulator DosR, which leads to the induction of the Dos dormancy regulon. NO, CO, and hypoxia induces the exact same 47-member transcriptional response in Mtb and is known as the Dos dormancy regulon. The Dos dormancy regulon encodes many genes of unknown function, as well for members of the nitrate reductase pathway, several universal stress proteins, and various transporter proteins. (To see this illustration in color the reader is referred to the web version of this article at www.liebertpub.com/ars).