FIGURE 7.
Hypothetical model depicting a role for CO in Mtb pathogenesis. Because numerous studies reported striking differences in local O2, NO, and CO concentrations in organs, tissues, and single cells (see supplemental note 3), the model predicts that gradients of O2, NO, or CO are sensed in conjunction by DosS and DosT, rather than independently. DosS is the preferred sensor of CO (thick blue arrow), whereas DosT is less capable (thin blue arrow) of inducing the Dos regulon. This contrasts with O2, which inhibits expression of the Dos regulon (blocked arrow), albeit not during hypoxia. The model predicts that a combination of microenvironmental O2, NO, or CO (overlapping circles) is crucial in modulating the state of the disease. Although modeling the above events in the context of chronic TB is technically difficult, the well established role of HO-1 in modulating apoptosis/necrosis, its anti-inflammatory properties (specifically the effect on tumor necrosis factor α), and the release of Fe(II) have significant implications for understanding the mechanism of Mtb persistence.