Increased vaccine efficacy against tuberculosis of recombinant Mycobacterium bovis bacille Calmette-Guérin mutants that secrete listeriolysin.
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.
Grode
Leander
L
Max Planck Institute for Infection Biology, Berlin, Germany.
Seiler
Peter
P
Baumann
Sven
S
Hess
Jürgen
J
Brinkmann
Volker
V
Nasser Eddine
Ali
A
Mann
Peggy
P
Goosmann
Christian
C
Bandermann
Silke
S
Smith
Debbie
D
Bancroft
Gregory J
GJ
Reyrat
Jean-Marc
JM
van Soolingen
Dick
D
Raupach
Bärbel
B
Kaufmann
Stefan H E
SH
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
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