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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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