Enhanced priming of adaptive immunity by a proapoptotic mutant of Mycobacterium tuberculosis.
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.
Hinchey
Joseph
J
Department of Microbiology and Immunology and Howard Hughes Medical Institute, Albert Einstein College of Medicine, New York, New York 10461, USA.
Lee
Sunhee
S
Jeon
Bo Y
BY
Basaraba
Randall J
RJ
Venkataswamy
Manjunatha M
MM
Chen
Bing
B
Chan
John
J
Braunstein
Miriam
M
Orme
Ian M
IM
Derrick
Steven C
SC
Morris
Sheldon L
SL
Jacobs
William R
WR
Porcelli
Steven A
SA
D000251:Adenosine Triphosphatases / Q000235:genetics; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D002460:Cell Line; D017353:Gene Deletion; D006168:Guinea Pigs; D006801:Humans; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D026901:Membrane Transport Proteins / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009163:Mycobacterium bovis / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D013482:Superoxide Dismutase / Q000235:genetics / Q000276:immunology; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D032581:Tuberculosis Vaccines / Q000235:genetics / Q000276:immunology*
D001426:Bacterial Proteins; D026901:Membrane Transport Proteins; D032581:Tuberculosis Vaccines; D013482:Superoxide Dismutase; D000251:Adenosine Triphosphatases; C442123:SecA2 protein, Mycobacterium