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J. Biol. Chem., Vol. 283, Issue 26, 18032-18039, June 27, 2008

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Heme Oxygenase-1-derived Carbon Monoxide Induces the Mycobacterium tuberculosis Dormancy Regulon^*

Ashwani Kumar, Jessy S. Deshane, David K. Crossman¹, Subhashini Bolisetty, Bo-Shiun Yan^¶, Igor Kramnik^¶, Anupam Agarwal, and Adrie J. C. Steyn²

From the Departments of Microbiology and Medicine, Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, Alabama 35294 and ^¶Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115

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 O₂, nitric oxide (NO), and carbon monoxide (CO) are regulatory ligands of DosS and DosT. Here, we show that in addition to O₂ 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, O₂, 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.

Received for publication, March 21, 2008 , and in revised form, April 8, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants AI058131 (to A. J. C. S.), DK59600, DK75532, and HL068157 (to A. A.), and HL059836 (to I. K.). This work was also supported by the University of Alabama at Birmingham (UAB) Center for AIDS Research (to A. J. C. S.), UAB Center for Free Radical Biology (to A. J. C. S.), and UAB Center for Emerging Infections and Emergency Preparedness (to A. J. C. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1 and supplemental information.

¹ Supported by NIAID, National Institutes of Health Training Grant T32 AI07041.

² To whom correspondence should be addressed: 845 19th St. South, BBRB Rm. 308, Birmingham, AL 35294. Tel.: 205-996-4805; Fax: 205-996-4800; E-mail: asteyn{at}uab.edu.

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