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Infection and Immunity, August 2009, p. 3258-3263, Vol. 77, No. 8
0019-9567/09/$08.00+0     doi:10.1128/IAI.01449-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Unique Roles of DosT and DosS in DosR Regulon Induction and Mycobacterium tuberculosis Dormancy {triangledown} ,{dagger}

Ryan W. Honaker, Rachel L. Leistikow, Iona L. Bartek, and Martin I. Voskuil*

University of Colorado Denver, School of Medicine, Department of Microbiology, P18-9115, 12800 East 19th Avenue, P.O. Box 6511, Aurora, Colorado 80045

Received 25 November 2008/ Returned for modification 5 February 2009/ Accepted 21 May 2009

In Mycobacterium tuberculosis, the sensor kinases DosT and DosS activate the transcriptional regulator DosR, resulting in the induction of the DosR regulon, which is important for anaerobic survival and perhaps latent infection. The individual and collective roles of these sensors have been postulated biochemically, but their roles in vivo have remained unclear. This work demonstrates distinct and additive roles for each sensor during anaerobic dormancy. Both sensors are necessary for wild-type levels of DosR regulon induction, and concomitantly, full induction of the regulon is required for wild-type anaerobic survival. In the anaerobic model, DosT plays an early role, responding to hypoxia. DosT then induces the regulon and with it DosS, which sustains and further induces the regulon. DosT then loses its functionality as oxygen becomes limited, and DosS alone maintains induction of the genes from that point forward. Thus, M. tuberculosis has evolved a system whereby it responds to hypoxic conditions in a stepwise fashion as it enters an anaerobic state.

* Corresponding author. Mailing address: University of Colorado Denver, School of Medicine, Department of Microbiology, P18-9115, 12800 East 19th Avenue, P.O. Box 6511, Aurora, CO 80045. Phone: (303) 724-4219. Fax: (303) 724-4226. E-mail: martin.voskuil{at}uchsc.edu

{triangledown} Published ahead of print on 1 June 2009.

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Editor: J. L. Flynn

Infection and Immunity, August 2009, p. 3258-3263, Vol. 77, No. 8
0019-9567/09/$08.00+0     doi:10.1128/IAI.01449-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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