Increased vaccine efficacy against tuberculosis of recombinant Mycobacterium bovis bacille Calmette-Guerin mutants that secrete listeriolysin

Abstract

The tuberculosis vaccine Mycobacterium bovis bacille Calmette-Guérin (BCG) was equipped with the membraneperforating listeriolysin (Hly) of Listeria monocytogenes, which was shown to improve protection against Mycobacterium tuberculosis. Following aerosol challenge, the Hly-secreting recombinant BCG (hly + rBCG) vaccine was shown to protect significantly better against aerosol infection with M. tuberculosis than did the parental BCG strain. The isogenic, urease C-deficient hly + rBCG (∆ureC hly + rBCG) vaccine, providing an intraphagosomal pH closer to the acidic pH optimum for Hly activity, exhibited still higher vaccine efficacy than parental BCG. ∆ureC hly + rBCG also induced profound protection against a member of the M. tuberculosis Beijing/W genotype family while parental BCG failed to do so consistently. Hly not only promoted antigen translocation into the cytoplasm but also apoptosis of infected macrophages. We concluded that superior vaccine efficacy of ∆ureC hly + rBCG as compared with parental BCG is primarily based on improved cross-priming, which causes enhanced T cell-mediated immunity.

Immunomodulatory effects of recombinant BCG expressing MSP-1C ofPlasmodium falciparumon LPS- or LPS+IFN-γ-stimulated J774A.1 cells

“…We demonstrate here for the first time that the rBCG strain increased macrophage phagocytic activity and induced higher production of NO, iNOS, and pro-inflammatory cytokines such as TNF-α and IL-1β than those produced by parent BCG-infected macrophages. The results are consistent with our previous finding 39 and other studies [46][47][48][49][50] demonstrating that a recombinant BCG is more potent in activating macrophages than parental BCG. These findings support our previous data showing that the rBCG vaccine capable of inducing a strong cell mediated and humoral immune responses in animal model.…”

“…79,80 On the other hand, other studies also suggested that this mechanism might involve macrophage apoptosis. 81,82 Indeed, Grode et al 48 also showed that a recombinant BCG secreting the listeriolysin (Hly) of Listeria monocytogenes capable of inducing apoptosis of the infected macrophages. Apoptosis involves the packaging of intracellular bacilli into membrane-bound vesicles, which facilitates antigen presentation and possibly enhances the antimicrobial efficacy of newly recruited macrophages to ensure efficient control of the spread and multiplication of the pathogen.…”

Next generation: tuberculosis vaccines that elicit protective CD8+T cells

“…Grode et al engineered urease C − BCG to express listeriolysin. Deleting urease C from BCG prevents alkalinization of the phagosome, leading to a more optimum pH for listeriolysin activity [47]. Vaccination with this engineered recombinant BCG strain led to improved protection against virulent M. tuberculosis as measured by lung CFU and survival.…”

Mycobacterial Lipopeptides Elicit CD4+ CTLs in Mycobacterium tuberculosis-Infected Humans

“…Several candidate vaccines have reached the level of clinical trials. Two vaccines improved classical BCG by inserting the secreted mycobacterial Ag85B (6) or by inserting listeriolysin to facilitate the escape of the bacilli from the phagosome into the cytoplasm (7). Another strategy follows the idea that secreted mycobacterial Ags from the Ag85 complex will induce protective memory T lymphocytes when given as fusion proteins (8 -10) or if expressed in a modified vaccinia virus Ankara (11).…”