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Infection and Immunity, June 2008, p. 2587-2593, Vol. 76, No. 6
0019-9567/08/$08.00+0     doi:10.1128/IAI.01235-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Mycobacterium bovis BCG Vaccine Strains Lack narK2 and narX Induction and Exhibit Altered Phenotypes during Dormancy{triangledown}

Ryan W. Honaker,1 Amanda Stewart,1 Stephanie Schittone,1 Angelo Izzo,2 Michèl R. Klein,3,{dagger} and Martin I. Voskuil1*

University of Colorado Denver, School of Medicine, Department of Microbiology, P18-9115, 12800 East 19th Avenue, P.O. Box 6511, Aurora, Colorado 80045,1 Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, 200 West Lake Street, 1682 Campus Delivery, Fort Collins, Colorado 80523-1682,2 Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands3

Received 7 September 2007/ Returned for modification 22 October 2007/ Accepted 13 March 2008

Mycobacterium tuberculosis is the causative agent of tuberculosis, a disease that affects one-third of the world's population. The sole extant vaccine for tuberculosis is the live attenuated Mycobacterium bovis bacillus Calmette-Guerin (BCG). We examined 13 representative BCG strains from around the world to ascertain their ability to express DosR-regulated dormancy antigens. These are known to be recognized by T cells of M. tuberculosis-infected individuals, especially those harboring latent infections. Differences in the expression of these antigens could be valuable for use as diagnostic markers to distinguish BCG vaccination from latent tuberculosis. We determined that all BCG strains were defective for the induction of two dormancy genes: narK2 (Rv1737c) and narX (Rv1736c). NarK2 is known to be necessary for nitrate respiration during anaerobic dormancy. Analysis of the narK2/X promoter region revealed a base substitution mutation in all tested BCG strains and M. bovis in comparison to the M. tuberculosis sequence. We also show that nitrate reduction by BCG strains during dormancy was greatly reduced compared to M. tuberculosis and varied between tested strains. Several dormancy regulon transcriptional differences were also identified among the strains, as well as variation in their growth and survival. These findings demonstrate defects in DosR regulon expression during dormancy and phenotypic variation between commonly used BCG vaccine strains.

* 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 24 March 2008.

Editor: A. J. Bäumler

{dagger} Present address: Center for Infectious Disease Control The Netherlands, National Institute for Public Health and the Environment, P.O. Box 1, 3720 BA Bilthoven, The Netherlands.

Infection and Immunity, June 2008, p. 2587-2593, Vol. 76, No. 6
0019-9567/08/$08.00+0     doi:10.1128/IAI.01235-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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