title: 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 (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.
authors.affiliation: Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Leander
authors.initials: L
authors.lastname: Grode
authors.forename: Peter
authors.initials: P
authors.lastname: Seiler
authors.forename: Sven
authors.initials: S
authors.lastname: Baumann
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hess
authors.forename: Volker
authors.initials: V
authors.lastname: Brinkmann
authors.forename: Ali
authors.initials: A
authors.lastname: Nasser Eddine
authors.forename: Peggy
authors.initials: P
authors.lastname: Mann
authors.forename: Christian
authors.initials: C
authors.lastname: Goosmann
authors.forename: Silke
authors.initials: S
authors.lastname: Bandermann
authors.forename: Debbie
authors.initials: D
authors.lastname: Smith
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Bancroft
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Reyrat
authors.forename: Dick
authors.initials: D
authors.lastname: van Soolingen
authors.forename: Bärbel
authors.initials: B
authors.lastname: Raupach
authors.forename: Stefan H E
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D001500:BCG Vaccine; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology; D001427:Bacterial Toxins / Q000378:metabolism*; D002478:Cells, Cultured; D002648:Child; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006460:Hemolysin Proteins; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008089:Listeria monocytogenes / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000276:immunology / Q000627:therapeutic use; D015996:Survival Rate; D014376:Tuberculosis / Q000517:prevention & control*; D014614:Vaccines, Synthetic
chemical_list: D001500:BCG Vaccine; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D011994:Recombinant Proteins; D014614:Vaccines, Synthetic; C038705:hlyA protein, Listeria monocytogenes