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Infection and Immunity, July 2004, p. 4200-4209, Vol. 72, No. 7
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.7.4200-4209.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Mycobacterium bovis BCG Urease Attenuates Major Histocompatibility Complex Class II Trafficking to the Macrophage Cell Surface

Division of Infectious Diseases, Department of Medicine, University of British Columbia, and Vancouver Coastal Health Institute, Vancouver, British Columbia, Canada,¹ Laboratoire d'Immunologie, Faculté des Sciences Dhar Mahraz, Université Mohamed Ben Abdallah, Fès, Morocco,² INSERM U570, Faculté de Médecine Necker-Enfants Malades, Paris, France³

Received 3 December 2003/ Returned for modification 12 January 2004/ Accepted 12 March 2004

We have previously shown that Mycobacterium tuberculosis attenuates cell surface expression of major histocompatibility complex class II molecules in response to gamma interferon (IFN-) by a mechanism dependent on intracellular sequestration of ,ß dimers. In this study we examined whether intracellular alkalinization due to mycobacterial urease could account for the defect in intracellular trafficking of class II molecules. Phagocytosis of wild-type Mycobacterium bovis BCG was associated with secretion of ammonia intracellularly, which increased substantially upon addition of exogenous urea to the culture medium. Increased intracellular ammonia, due to urea degradation by the bacterium, correlated with inhibition of class II surface expression. Conversely, no ammonia was detected in cells infected with a urease-negative mutant strain of M. bovis BCG, which also displayed a reduced effect on surface expression of class II molecules. A direct cause-effect relationship between urease and class II molecule trafficking was established with experiments where cells ingesting beads coated with purified urease showed an increased ammonia level and decreased surface expression of class II in response to IFN-. In contrast to BCG, infection of macrophages with Mycobacterium smegmatis, which expresses relatively greater urease activity in cell-free culture, had a marginal effect on both the intracellular level of ammonia and class II expression. The limited effect of M. smegmatis was consistent with a failure to resist intracellular killing, suggesting that urease alone is not sufficient to resist macrophage microbicidal mechanisms and that this is required for a more distal effect on cell regulation. Our results demonstrate that alkalinization of critical intracellular organelles by pathogenic mycobacteria expressing urease contributes significantly to the intracellular retention of class II dimers.

Editor: J. B. Bliska

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