Anaerobic nitrate reductase (narGHJI) activity of Mycobacterium bovis BCG in vitro and its contribution to virulence in immunodeficient mice

Mycobacterium tuberculosis and Mycobacterium bovis cause tuberculosis, which is responsible for the deaths of more people each year than any other bacterial infectious disease. Disseminated disease with Mycobacterium bovis BCG, the only currently available vaccine against tuberculosis, occurs in imm...

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Published in:	Molecular microbiology Vol. 35; no. 5; pp. 1017 - 1025
Main Authors:	Weber, Isabel, Fritz, Christian, Ruttkowski, Silvia, Kreft, Andreas, Bange, Franz‐Christoph
Format:	Journal Article
Language:	English
Published:	Oxford, UK Blackwell Science Ltd 01-03-2000 Blackwell Publishing Ltd
Subjects:	Animals Base Sequence Cloning, Molecular DNA Primers Mice Mice, Inbred BALB C Mice, SCID Mutation Mycobacterium bovis Mycobacterium bovis - growth & development Mycobacterium bovis - pathogenicity Mycobacterium smegmatis - genetics Mycobacterium tuberculosis - genetics narG gene Nitrate Reductase Nitrate Reductases - genetics Nitrate Reductases - metabolism Phenotype Virulence
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Summary:	Mycobacterium tuberculosis and Mycobacterium bovis cause tuberculosis, which is responsible for the deaths of more people each year than any other bacterial infectious disease. Disseminated disease with Mycobacterium bovis BCG, the only currently available vaccine against tuberculosis, occurs in immunocompetent and immunodeficient individuals. Although mycobacteria are obligate aerobes, they are thought to face an anaerobic environment during infection, notably inside abscesses and granulomas. The purpose of this study was to define a metabolic pathway that could allow mycobacteria to exist under these conditions. Recently, the complete genome of M. tuberculosis has been sequenced, and genes homologous to an anaerobic nitrate reductase (narGHJI), an enzyme allowing nitrate respiration when oxygen is absent, were found. Here, we show that the narGHJI cluster of M. tuberculosis is functional as it conferred anaerobic nitrate reductase activity to Mycobacterium smegmatis. A narG mutant of M. bovis BCG was generated by targeted gene deletion. The mutant lacked the ability to reduce nitrate under anaerobic conditions. Both mutant and M. bovis BCG wild type grew equally well under aerobic conditions in vitro. Histology of immunodeficient mice (SCID) infected with M. bovis BCG wild type revealed large granulomas teeming with acid‐fast bacilli; all mice showed signs of clinical disease after 50 days and succumbed after 80 days. In contrast, mice infected with the mutant had smaller granulomas containing fewer bacteria; these mice showed no signs of clinical disease after more than 200 days. Thus, it seems that nitrate respiration contributes significantly to virulence of M. bovis BCG in immunodeficient SCID mice.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0950-382X 1365-2958
DOI:	10.1046/j.1365-2958.2000.01794.x