title: Disruption of the SapM locus in Mycobacterium bovis BCG improves its protective efficacy as a vaccine against M. tuberculosis.
abstract: Mycobacterium bovis bacille Calmette-Guerin (BCG) provides only limited protection against pulmonary tuberculosis. We tested the hypothesis that BCG might have retained immunomodulatory properties from its pathogenic parent that limit its protective immunogenicity. Mutation of the molecules involved in immunomodulation might then improve its vaccine potential. We studied the vaccine potential of BCG mutants deficient in the secreted acid phosphatase, SapM, or in the capping of the immunomodulatory ManLAM cell wall component with α-1,2-oligomannoside. Both systemic and intratracheal challenge of mice with Mycobacterium tuberculosis following vaccination showed that the SapM mutant, compared to the parental BCG vaccine, provided better protection: it led to longer-term survival. Persistence of the SapM-mutated BCG in vivo resembled that of the parental BCG indicating that this mutation will likely not compromise the safety of the BCG vaccine. The SapM mutant BCG vaccine was more effective than the parental vaccine in inducing recruitment and activation of CD11c(+) MHC-II(int) CD40(int) dendritic cells (DCs) to the draining lymph nodes. Thus, SapM acts by inhibiting recruitment of DCs and their activation at the site of vaccination.
authors.affiliation: Unit for Medical Biotechnology, Department for Molecular Biomedical Research, Ghent, Belgium. nele.festjens@dmbr.vib-ugent.be
authors.forename: Nele
authors.initials: N
authors.lastname: Festjens
authors.forename: Pieter
authors.initials: P
authors.lastname: Bogaert
authors.forename: Anjana
authors.initials: A
authors.lastname: Batni
authors.forename: Erica
authors.initials: E
authors.lastname: Houthuys
authors.forename: Evelyn
authors.initials: E
authors.lastname: Plets
authors.forename: Dieter
authors.initials: D
authors.lastname: Vanderschaeghe
authors.forename: Bram
authors.initials: B
authors.lastname: Laukens
authors.forename: Bob
authors.initials: B
authors.lastname: Asselbergh
authors.forename: Eef
authors.initials: E
authors.lastname: Parthoens
authors.forename: Riet
authors.initials: R
authors.lastname: De Rycke
authors.forename: Monique A
authors.initials: MA
authors.lastname: Willart
authors.forename: Peggy
authors.initials: P
authors.lastname: Jacques
authors.forename: Dirk
authors.initials: D
authors.lastname: Elewaut
authors.forename: Peter
authors.initials: P
authors.lastname: Brouckaert
authors.forename: Bart N
authors.initials: BN
authors.lastname: Lambrecht
authors.forename: Kris
authors.initials: K
authors.lastname: Huygen
authors.forename: Nico
authors.initials: N
authors.lastname: Callewaert
mesh_terms: D000135:Acid Phosphatase / Q000235:genetics* / Q000276:immunology; D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D001426:Bacterial Proteins / Q000235:genetics* / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009163:Mycobacterium bovis / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000502:physiology; D017384:Sequence Deletion; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*
chemical_list: D001500:BCG Vaccine; D001426:Bacterial Proteins; D016207:Cytokines; D000135:Acid Phosphatase