Abstract
The inhibition of apoptosis of infected host cells is a well-known but poorly understood function of pathogenic mycobacteria. We show that inactivation of the secA2 gene in Mycobacterium tuberculosis, which encodes a component of a virulence-associated protein secretion system, enhanced the apoptosis of infected macrophages by diminishing secretion of mycobacterial superoxide dismutase. Deletion of secA2 markedly increased priming of antigen-specific CD8(+) T cells in vivo, and vaccination of mice and guinea pigs with a secA2 mutant significantly increased resistance to M. tuberculosis challenge compared with standard M. bovis bacille Calmette-Guérin vaccination. Our results define a mechanism for a key immune evasion strategy of M. tuberculosis and provide what we believe to be a novel approach for improving mycobacterial vaccines.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphatases* / genetics
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Animals
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Bacterial Proteins* / genetics
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Cell Line
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Gene Deletion*
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Guinea Pigs
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Humans
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Macrophages / immunology*
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Macrophages / microbiology
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Membrane Transport Proteins* / genetics
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Mice
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Mice, Inbred BALB C
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Mycobacterium bovis / immunology
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Mycobacterium tuberculosis / genetics
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Mycobacterium tuberculosis / immunology*
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Mycobacterium tuberculosis / pathogenicity
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Superoxide Dismutase / genetics
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Superoxide Dismutase / immunology
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Tuberculosis / genetics
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Tuberculosis / immunology*
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Tuberculosis / prevention & control
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Tuberculosis Vaccines / genetics
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Tuberculosis Vaccines / immunology*
Substances
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Bacterial Proteins
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Membrane Transport Proteins
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Tuberculosis Vaccines
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Superoxide Dismutase
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Adenosine Triphosphatases
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SecA2 protein, Mycobacterium