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Infection and Immunity, October 2001, p. 5967-5973, Vol. 69, No. 10
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.10.5967-5973.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Silencing of Oxidative Stress Response in Mycobacterium tuberculosis: Expression Patterns of ahpC in Virulent and Avirulent Strains and Effect of ahpC Inactivation

B. Springer,1 S. Master,2 P. Sander,1 T. Zahrt,2 M. McFalone,2 J. Song,2 K. G. Papavinasasundaram,3 M. J. Colston,3 E. Boettger,1,4 and V. Deretic2,5,*

Institute for Medical Microbiology, Medizinische Hochschule, 30625 Hannover, Germany1; Department of Microbiology and Immunology2 and Program in Cellular and Molecular Biology,5 University of Michigan Medical School, Ann Arbor, Michigan 48109-0620; Division of Mycobacterial Research, The National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom3; and Institute for Medical Microbiology, Universitat Zürich, CH 8028 Zürich, Switzerland4

Received 16 January 2001/Returned for modification 20 March 2001/Accepted 21 June 2001

Intracellular pathogens such as Mycobacterium tuberculosis are able to survive in the face of antimicrobial products generated by the host cell in response to infection. The product of the alkyl hydroperoxide reductase gene (ahpC) of M. tuberculosis is thought to be involved in protecting the organism against both oxidative and nitrosative stress encountered within the infected macrophage. Here we report that, contrary to expectations, ahpC expression in virulent strains of M. tuberculosis and Mycobacterium bovis grown in vitro is repressed, often below the level of detection, whereas expression in the avirulent vaccine strain M. bovis BCG is constitutively high. The repression of the ahpC gene of the virulent strains is independent of the naturally occurring lesions of central regulator oxyR. Using a green fluorescence protein vector (gfp)-ahpC reporter construct we present data showing that repression of ahpC of virulent M. tuberculosis also occurred during growth inside macrophages, whereas derepression in BCG was again seen under identical conditions. Inactivation of ahpC on the chromosome of M. tuberculosis by homologous recombination had no effect on its growth during acute infection in mice and did not affect in vitro sensitivity to H2O2. However, consistent with AhpC function in detoxifying organic peroxides, sensitivity to cumene hydroperoxide exposure was increased in the ahpC::Kmr mutant strain. The preservation of a functional ahpC gene in M. tuberculosis in spite of its repression under normal growth conditions suggests that, while AhpC does not play a significant role in establishing infection, it is likely to be important under certain, as yet undefined conditions. This is supported by the observation that repression of ahpC expression in vitro was lifted under conditions of static growth.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, University of Michigan Medical School, 5641 Medical Science Building II, Ann Arbor, MI 48109-0620. Phone: (734) 763-1580. Fax: (734) 647-6243. E-mail: Deretic{at}umich.edu.

Infection and Immunity, October 2001, p. 5967-5973, Vol. 69, No. 10
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.10.5967-5973.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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