Search

It has been proposed that Mycobacterium tuberculosis virulent strains inhibit apoptosis and trigger cell death by necrosis of host macrophages to evade innate immunity, while non-virulent strains induce typical apoptosis activating a protective host response. As part of the characterization of a novel tuberculosis vaccine candidate, the M. tuberculosis phoP mutant SO2, we sought to evaluate its potential to induce host cell death. The parental M. tuberculosis MT103 strain and the current vaccine against tuberculosis Bacillus Calmette-Guérin (BCG) were used as comparators in mouse models in vitro and in vivo. Our data reveal that attenuated SO2 was unable to induce apoptotic events neither in mouse macrophages in vitro nor during lung infection in vivo. In contrast, virulent MT103 triggers typical apoptotic events with phosphatidylserine exposure, caspase-3 activation and nuclear condensation and fragmentation. BCG strain behaved like SO2 and did not induce apoptosis. A clonogenic survival assay confirmed that viability of BCG- or SO2-infected macrophages was unaffected. Our results discard apoptosis as the protective mechanism induced by SO2 vaccine and provide evidence for positive correlation between classical apoptosis induction and virulent strains, suggesting apoptosis as a possible virulence determinant during M. tuberculosis infection.

Background: The need for an effective vaccine against human tuberculosis has driven the development of different candidates and vaccination strategies. Novel live attenuated vaccines are being developed that promise greater safety and efficacy than BCG against tuberculosis. We combined BCG with the vaccine MTBVAC to evaluate whether the efficacy of either vaccine would be affected upon revaccination.Methods: In a well-established guinea pig model of aerosol infection with Mycobacterium tuberculosis, BCG and MTBVAC delivered via various prime-boost combinations or alone were compared. Efficacy was determined by a reduction in bacterial load 4 weeks after challenge.Results: Efficacy data suggests MTBVAC-associated immunity is longer lasting than that of BCG when given as a single dose. Long and short intervals between BCG prime and MTBVAC boost resulted in improved efficacy in lungs, compared with BCG given alone. A shorter interval between MTBVAC prime and BCG boost resulted in improved efficacy in lungs, compared with BCG given alone. A longer interval resulted in protection equivalent to that of BCG given alone.Conclusions: These data indicate that, rather than boosting the waning efficacy of BCG, a vaccination schedule involving a combination of the 2 vaccines yielded stronger immunity to M. tuberculosis infection. This work supports development of MTBVAC use as a revaccination strategy to improve on the effects of BCG in vaccinated people living in tuberculosis-endemic countries. [ABSTRACT FROM AUTHOR]

Granzyme A, a serine protease expressed in the granules of cytotoxic T and Natural Killer cells, is involved in the generation of pro-inflammatory cytokines by macrophages. Granzyme A has been described to induce in macrophages in vitro the activation of pro-inflammatory pathways that impair intracellular mycobacterial replication. In the present study, we explored the physiological relevance of Granzyme A in the control of pulmonary Mycobacterium tuberculosis infection in vivo. Our results show that, even though Granzyme A is expressed by cytotoxic cells from mouse lungs during pulmonary infection, its deficiency in knockout mice does not have an effect in the control of M. tuberculosis infection. In addition our findings indicate that absence of Granzyme A does not affect the protection conferred by the live-attenuated M. tuberculosis vaccine MTBVAC. Altogether, our findings are in apparent contradiction with previously published in vitro results and suggest that Granzyme A does not have a crucial role in vivo in the protective response to tuberculosis. [ABSTRACT FROM AUTHOR]

Some of the most promising novel tuberculosis vaccine strategies currently under development are based on respiratory vaccination, mimicking the natural route of infection. In this work, we have compared pulmonary and subcutaneous delivery of BCG vaccine in the tuberculosis-susceptible DBA/2 mouse strain, a model in which parenterally administered BCG vaccine does not protect against tuberculosis. Our data show that intranasally but not subcutaneously administered BCG confers robust protection against pulmonary tuberculosis challenge. In addition, our results indicate that pulmonary vaccination triggers a Mycobacterium tuberculosis-specific mucosal immune response orchestrated by interleukin 17A (IL-17A). Thus, IL-17A neutralization in vivo reduces protection and abrogates M. tuberculosis-specific immunoglobulin A (IgA) secretion to respiratory airways and lung expression of polymeric immunoglobulin receptor induced following intranasal vaccination. Together, our results demonstrate that pulmonary delivery of BCG can overcome the lack of protection observed when BCG is given parenterally, suggesting that respiratory tuberculosis vaccines could have an advantage in tuberculosis-endemic countries, where intradermally administered BCG has inefficient effectiveness against pulmonary tuberculosis. [ABSTRACT FROM AUTHOR]