Enhanced priming of adaptive immunity by a proapoptotic mutant of Mycobacterium tuberculosis
Joseph Hinchey, … , William R. Jacobs Jr., Steven A. Porcelli
Joseph Hinchey, … , William R. Jacobs Jr., Steven A. Porcelli
Published August 1, 2007
Citation Information: J Clin Invest. 2007;117(8):2279-2288. https://doi.org/10.1172/JCI31947.
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Research Article

Enhanced priming of adaptive immunity by a proapoptotic mutant of Mycobacterium tuberculosis

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.

Authors

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

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Figure 3

Augmented memory T cell populations following immunization with ΔsecA2.

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Augmented memory T cell populations following immunization with ΔsecA2. ...
C57BL/6 mice were adoptively transferred with 5 × 105 OT-I splenocytes 24 hours prior to vaccination by subcutaneous infection with either H37Rv-OVA or ΔsecA2-OVA. The animals were sacrificed 2, 4, 8, and 20 weeks after vaccination, and splenocytes were stained for 5-color fluorescence analysis using antibodies specific to Thy1.2, B220, CD62L, and CD44 plus SIINFEKL-loaded H-2Kb tetramer. (A) FACS analysis of total B220– events among 1.5 × 106 total lymphocytes, showing proportions of Thy1.2+ cells staining with tetramer. (B) Dot plots show expression of CD44 and CD62L on cells gated for tetramer staining as in A from representative mice sacrificed 2 weeks after infection with the indicated bacterial strains. The graphs show percentages of total B220– lymphocytes staining with tetramer (Tet) and expressing either high or low levels of CD62L at each time point after vaccination. Filled squares represent ΔsecA2-vaccinated mice and open squares, H37Rv-OVA–vaccinated mice. Each symbol represents mean and SD for groups of 2 or 3 mice.