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Microbiology 148 (2002), 3139-3144
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Microbiology (2002), 148, 3139-3144.
© 2002 Society for General Microbiology

Molecular Genetics and Immunobiology of Mycobacteria

Oxidative stress response genes in Mycobacterium tuberculosis: role of ahpC in resistance to peroxynitrite and stage-specific survival in macrophages

S. S. Master1, B. Springer3, P. Sander3, E. C. Boettger4, V. Deretic1 and G. S. Timmins2

Department of Molecular Genetics and Microbiology1 and Department of Pharmacy2, University of New Mexico Health Sciences Center, 915 Camino de Salud, Albuquerque, NM 87131, USA
Institute for Medical Microbiology, Medizinische Hochschule, 30625, Hannover, Germany3
Institute of Medical Microbiology, University of Zurich, CH-8028 Zurich, Switzerland4

Author for correspondence: V. Deretic. Tel: +1 505 272 0291. Fax: +1 505 272 6029. e-mail: vderetic{at}salud.unm.edu

The Mycobacterium tuberculosis ahpC gene, encoding the mycobacterial orthologue of alkylhydroperoxide reductase, undergoes an unusual regulatory cycle. The levels of AhpC alternate between stages of expression silencing in virulent strains grown as aerated cultures, secondary to a natural loss of the regulatory oxyR function in all strains of the tubercle bacillus, and expression activation in static bacilli by a yet undefined mechanism. The reasons for this unorthodox regulatory cycle controlling expression of an antioxidant factor are currently not known. In this work, M. tuberculosis H37Rv and Mycobacterium smegmatis mc2155 ahpC knockout mutants were tested for sensitivity to reactive nitrogen intermediates, in particular peroxynitrite, a highly reactive combinatorial product of reactive nitrogen and oxygen species, and sensitivity to bactericidal mechanisms in resting and activated macrophages. Both M. tuberculosis ahpC::Kmr and M. smegmatis ahpC::Kmr showed increased susceptibility to peroxynitrite. In contrast, inactivation of ahpC in M. tuberculosis did not cause increased sensitivity to donors of NO alone. M. tuberculosis ahpC::Kmr also showed decreased survival in unstimulated macrophages, but the effect was no longer detectable upon IFN{gamma} activation. These studies establish a specific role for ahpC in antioxidant defences involving peroxynitrite and most likely additional cidal mechanisms in macrophages, with the regulatory cycle likely contributing to survival upon coming out of the stationary phase during dormancy (latent infection) or upon transmission to a new host.

Keywords: M. tuberculosis, nitric oxide, ahpC, peroxynitrite, latency

Abbreviations: DETA nonoate, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)aminio]diazen-1-ium-1,2-diolate)




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