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. 2002 Jan;70(1):286-91.
doi: 10.1128/IAI.70.1.286-291.2002.

Dependence of Mycobacterium bovis BCG on anaerobic nitrate reductase for persistence is tissue specific

Christian Fritz  1 , Silvia Maass, Andreas Kreft, Franz-Christoph Bange
Affiliations

Dependence of Mycobacterium bovis BCG on anaerobic nitrate reductase for persistence is tissue specific

Christian Fritz et al. Infect Immun. 2002 Jan.

Abstract

Mycobacterium bovis BCG, the only presently available vaccine against tuberculosis, was obtained from virulent M. bovis after serial passages in vitro. The vaccine strain retained at least some of its original virulence, as it persists in immune-competent hosts and occasionally may cause fatal disease in immune-deficient hosts. Mycobacterial persistence in vivo is thought to depend on anaerobic metabolism, an apparent paradox since all mycobacteria are obligate aerobes. Here we report that M. bovis BCG lacking anaerobic nitrate reductase (NarGHJI), an enzyme essential for nitrate respiration, failed to persist in the lungs, liver, and kidneys of immune-competent (BALB/c) mice. In immune-deficient (SCID) mice, however, bacilli caused chronic infection despite disruption of narG, even if growth of the mutant was severely impaired in lungs, liver, and kidneys. Persistence and growth of BCG in the spleens of either mouse strain appeared largely unaffected by lack of anaerobic nitrate reductase, indicating that the role of the enzyme in pathogenesis is tissue specific. These data suggest first that anaerobic nitrate reduction is essential for metabolism of M. bovis BCG in immune-competent but not immune-deficient mice and second that its role in mycobacterial disease is tissue specific, both of which are observations with important implications for pathogenesis of mycobacteria and vaccine development.

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Figures

FIG. 1.
FIG. 1.
Wild-type (closed symbols) and ΔnarG mutant (open symbols) bacteria were enumerated by plating for counts of CFU. Bacteria were cultured in medium without nitrate (circles) and with nitrate (triangles) under anaerobic conditions.
FIG. 2.
FIG. 2.
Histology of the lungs of SCID mice (a and b) and BALB/c mice (c and d). Mice were infected with 106 CFU of wild-type (a and c) or ΔnarG (IW1) (b and d) bacteria. SCID mice succumbed to the infection after 14 weeks (a) and 37 weeks (b), whereas BALB/c mice were sacrificed 31 weeks after infection (c and d) and sections of the lung were stained with Ziehl-Neelsen and counterstained with hematoxylin.
FIG. 3.
FIG. 3.
Bacteria in the lungs (a), livers (b), and kidneys (c) of intravenously infected SCID mice were enumerated by plating for counts of CFU. Bacterial loads in mice infected with 106 CFU of ΔnarG (open circles) or wild-type (closed circles) bacteria are shown.
FIG. 4.
FIG. 4.
Bacteria in the lungs (a), livers (b), and kidneys (c) of intravenously infected BALB/c mice were enumerated by plating for counts of CFU. Bacterial loads in mice infected with 106 CFU of ΔnarG (open circles) or wild-type (closed circles) bacteria are shown.
FIG. 5.
FIG. 5.
Bacteria in the spleens of intravenously infected SCID (a and b) and BALB/c (c) mice were enumerated by plating for counts of CFU. Bacterial loads in mice infected with ΔnarG (open circles) or wild-type (closed circles) bacteria are shown. Mice were infected with 106 CFU (a and c) or 104 CFU (b) of bacteria.
See this image and copyright information in PMC

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