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

• Published in: The Journal of clinical investigation 2005-09, Vol.115 (9), p.2472-2479
• Main Authors: Grode, Leander, Seiler, Peter, Baumann, Sven, Hess, Jürgen, Brinkmann, Volker, Nasser Eddine, Ali, Mann, Peggy, Goosmann, Christian, Bandermann, Silke, Smith, Debbie, Bancroft, Gregory J, Reyrat, Jean-Marc, van Soolingen, Dick, Raupach, Bärbel, Kaufmann, Stefan H E
• Format: Article
• Language: English
• Subjects: Acidification; Adult; Aerosols; Animals; Antigens; Apoptosis; Bacterial Proteins - genetics; Bacterial Proteins - immunology; Bacterial Toxins - metabolism; BCG Vaccine; Biomedical research; Blood; Cells, Cultured; Child; Genotype & phenotype; Heat-Shock Proteins - metabolism; Hemolysin Proteins; Humans; Hydrogen-Ion Concentration; Listeria; Listeria monocytogenes - immunology; Listeria monocytogenes - metabolism; Lymphocytes; Macrophages - cytology; Macrophages - metabolism; Mice; Mice, SCID; Mycobacterium tuberculosis - immunology; Mycobacterium tuberculosis - metabolism; Recombinant Proteins - immunology; Recombinant Proteins - therapeutic use; Survival Rate; Tuberculosis; Tuberculosis - prevention & control; Vaccines; Vaccines, Synthetic
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI24617

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 (DeltaureC hly+ rBCG) vaccine, providing an intraphagosomal pH closer to the acidic pH optimum for Hly activity, exhibited still higher vaccine efficacy than parental BCG. DeltaureC 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 DeltaureC hly+ rBCG as compared with parental BCG is primarily based on improved cross-priming, which causes enhanced T cell-mediated immunity.