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.
Joseph Hinchey, Sunhee Lee, Bo Y. Jeon, Randall J. Basaraba, Manjunatha M. Venkataswamy, Bing Chen, John Chan, Miriam Braunstein, Ian M. Orme, Steven C. Derrick, Sheldon L. Morris, William R. Jacobs Jr., Steven A. Porcelli