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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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 5

Protective immunity against virulent M. tuberculosis challenge in guinea pigs following vaccination with ΔsecA2.

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Protective immunity against virulent M. tuberculosis challenge in guinea...
(A) Outbred Hartley guinea pigs were vaccinated intradermally with saline, BCG, or ΔsecA2 (n = 5 animals per group) and challenged by aerosol 2 months later with 10–30 CFU of virulent M. tuberculosis H37Rv. Graphs show SEM of CFU of M. tuberculosis in lung, spleen, and mediastinal lymph nodes at 1 and 2 months after challenge for naive (white bars), BCG-vaccinated (gray bars), or ΔsecA2-vaccinated (black bars) animals (CFU counts obtained from a minimum of 3 and in most instances 5 animals; an exception was 2-month spleen CFU for BCG-vaccinated animals, in which counts were obtained from only 1 animal for technical reasons). (B) Quantitative scoring of histopathology graphed as the SEM of the rank scores for the groups of guinea pigs vaccinated and challenged as described in A. Images show representative low-power (×25) views of H&E-stained sections of mediastinal lymph nodes harvested from each group at 1 or 2 months after challenge. Scale bars: 1 mm. *P < 0.05, **P < 0.01, †P < 0.001 compared with unvaccinated group or between bracketed groups; 1-way ANOVA with Tukey’s post-hoc test.