title: Virulence factor SenX3 is the oxygen-controlled replication switch of Mycobacterium tuberculosis.
abstract: OBJECTIVE
  Morphogenetic switching between the replicating and nonreplicating states of Mycobacterium tuberculosis is regulated by oxygen, nitric oxide, and carbon monoxide levels. The mechanisms by which M. tuberculosis senses these diatomic gases remain poorly understood. In this study, we have examined whether virulence factor SenX3 plays any role in oxygen sensing.
  
  
  RESULTS
  In this study, we demonstrate that the virulence factor SenX3 is a heme protein that acts as a three-way sensor with three levels of activity. The oxidation of SenX3 heme by oxygen leads to the activation of its kinase activity, whereas the deoxy-ferrous state confers a moderate kinase activity. The binding of nitric oxide and carbon monoxide inhibits kinase activity. Consistent with these biochemical properties, the SenX3 mutant of M. tuberculosis is capable of attaining a nonreplicating persistent state in response to hypoxic stress, but its regrowth on the restoration of ambient oxygen levels is significantly attenuated compared with the wild-type and the complemented mutant strains. Furthermore, the presence of signaling concentrations of nitric oxide and carbon monoxide was able to inhibit the regrowth of M. tuberculosis in response to ambient oxygen levels.
  
  
  CONCLUSIONS
  Evidence presented in this study delineates a plausible mechanism explaining the oxygen-induced reactivation of tuberculosis diseases in humans after many years of latent infection. Furthermore, this study implicates nitric oxide and carbon monoxide in the inhibition of mycobacterial growth from the nonreplicating state.
authors.affiliation: Department of Infectious Diseases and Immunity, Council of Scientific and Industrial Research, Institute of Microbial Technology , Chandigarh, India .
authors.forename: Nisha
authors.initials: N
authors.lastname: Singh
authors.forename: Ashwani
authors.initials: A
authors.lastname: Kumar
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D002248:Carbon Monoxide / Q000378:metabolism; D004261:DNA Replication; D004269:DNA, Bacterial / Q000378:metabolism*; D006420:Hemeproteins / Q000378:metabolism; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D010770:Phosphotransferases / Q000737:chemistry / Q000378:metabolism*; D037521:Virulence Factors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D004269:DNA, Bacterial; D006420:Hemeproteins; D037521:Virulence Factors; D009569:Nitric Oxide; D002248:Carbon Monoxide; D010770:Phosphotransferases; C110607:SenX3 protein, Mycobacterium; D010100:Oxygen