title: Heme oxygenase-1-derived carbon monoxide induces the Mycobacterium tuberculosis dormancy regulon.
abstract: The mechanisms that allow Mycobacterium tuberculosis (Mtb) to persist in human tissue for decades and to then abruptly cause disease are not clearly understood. Regulatory elements thought to assist Mtb to enter such a state include the heme two-component sensor kinases DosS and DosT and the cognate response regulator DosR. We have demonstrated previously that O(2), nitric oxide (NO), and carbon monoxide (CO) are regulatory ligands of DosS and DosT. Here, we show that in addition to O(2) and NO, CO induces the complete Mtb dormancy (Dos) regulon. Notably, we demonstrate that CO is primarily sensed through DosS to induce the Dos regulon, whereas DosT plays a less prominent role. We also show that Mtb infection of macrophage cells significantly increases the expression, protein levels, and enzymatic activity of heme oxygenase-1 (HO-1, the enzyme that produces CO), in an NO-independent manner. Furthermore, exploiting HO-1(+/+) and HO-1(-/-) bone marrow-derived macrophages, we demonstrate that physiologically relevant levels of CO induce the Dos regulon. Finally, we demonstrate that increased HO-1 mRNA and protein levels are produced in the lungs of Mtb-infected mice. Our data suggest that during infection, O(2), NO, and CO are being sensed concurrently rather than independently via DosS and DosT. We conclude that CO, a previously unrecognized host factor, is a physiologically relevant Mtb signal capable of inducing the Dos regulon, which introduces a new paradigm for understanding the molecular basis of Mtb persistence.
authors.affiliation: Department of Microbiology, Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Ashwani
authors.initials: A
authors.lastname: Kumar
authors.forename: Jessy S
authors.initials: JS
authors.lastname: Deshane
authors.forename: David K
authors.initials: DK
authors.lastname: Crossman
authors.forename: Subhashini
authors.initials: S
authors.lastname: Bolisetty
authors.forename: Bo-Shiun
authors.initials: BS
authors.lastname: Yan
authors.forename: Igor
authors.initials: I
authors.lastname: Kramnik
authors.forename: Anupam
authors.initials: A
authors.lastname: Agarwal
authors.forename: Adrie J C
authors.initials: AJ
authors.lastname: Steyn
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D002248:Carbon Monoxide / Q000737:chemistry*; D005786:Gene Expression Regulation; D015964:Gene Expression Regulation, Bacterial; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010100:Oxygen / Q000378:metabolism; D006656:Protamine Kinase / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D001426:Bacterial Proteins; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; C506260:DevS protein, Mycobacterium tuberculosis; D006656:Protamine Kinase; D010100:Oxygen