Increased vaccine efficacy against tuberculosis of recombinant Mycobacterium bovis bacille Calmette-Guérin mutants that secrete listeriolysin
Leander Grode, … , Bärbel Raupach, Stefan H.E. Kaufmann
Leander Grode, … , Bärbel Raupach, Stefan H.E. Kaufmann
Published September 1, 2005
Citation Information: J Clin Invest. 2005;115(9):2472-2479. https://doi.org/10.1172/JCI24617.
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Increased vaccine efficacy against tuberculosis of recombinant Mycobacterium bovis bacille Calmette-Guérin mutants that secrete listeriolysin

Abstract

The tuberculosis vaccine Mycobacterium bovis bacille Calmette-Guérin (BCG) was equipped with the membrane-perforating 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 (ΔureC hly+ rBCG) vaccine, providing an intraphagosomal pH closer to the acidic pH optimum for Hly activity, exhibited still higher vaccine efficacy than parental BCG. ΔureC 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 ΔureC hly+ rBCG as compared with parental BCG is primarily based on improved cross-priming, which causes enhanced T cell–mediated immunity.

Authors

Leander Grode, Peter Seiler, Sven Baumann, Jürgen Hess, Volker Brinkmann, Ali Nasser Eddine, Peggy Mann, Christian Goosmann, Silke Bandermann, Debbie Smith, Gregory J. Bancroft, Jean-Marc Reyrat, Dick van Soolingen, Bärbel Raupach, Stefan H.E. Kaufmann

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Figure 3

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Greater protection against M. tuberculosis Beijing/W by vaccination with...
Greater protection against M. tuberculosis Beijing/W by vaccination with ΔureC hly+ rBCG. BALB/c mice were vaccinated with ΔureC hly+ rBCG (diamonds) or parental BCG (circles) or left naive (squares). At day 120 after vaccination, mice were aerosol challenged with 200 CFU of M. tuberculosis Beijing/W. M. tuberculosis load in lung was determined at the indicated time points. Upper panel: lung, P < 0.001 (Mann-Whitney U test) for ΔureC hly+ rBCG compared with parental BCG at day 200 p.i.; and P < 0.05 (Friedman test) for the whole observation period. Lower panel: spleen, P < 0.001 (Mann Whitney U test) for ΔureC hly+ rBCG compared with parental BCG at day 200 p.i. Shown is 1 representative experiment of 2. The mean of results for 7 mice is shown (± SEM).