title: M.tuberculosis mutants lacking oxygenated mycolates show increased immunogenicity and protective efficacy as compared to M. bovis BCG vaccine in an experimental mouse model.
abstract: The existing vaccine against tuberculosis (M. bovis BCG) exerts some protection against the extrapulmonary forms of the disease, particularly in young children, but is not very effective against the pulmonary form of TB, which often results from the reactivation of a latent M. tuberculosis (M.tb)infection. Among the new approaches in TB vaccine development, live attenuated M.tb mutants are a promising new avenue. Here we report on the vaccine potential of two highly attenuated M.tb mutants, MGM1991 and M.tbhma::hyg (HMA), lacking all oxygenated mycolates in their cell wall. In C57BL/6 mice, stronger Th1 (IFN-γ, IL-2 and TNF-α) and IL-17 responses could be induced following subcutaneous vaccination with either of the two mutants, than following vaccination with M. bovis BCG. Significantly more mycobacteria specific IFN-γ producing CD4(+) and particularly CD8(+) T cells could be detected by intracellular cytokine staining in mice vaccinated with the M.tb mutants. Finally, vaccination with either of the two mutants conferred stronger protection against intratracheal M.tb challenge than vaccination with BCG, as indicated by reduced bacterial replication in lungs at 4 to 12 weeks after challenge. Protection against M. tb dissemination, as indicated by reduced bacterial numbers in spleen, was comparable for both mutants to protection conferred by BCG.
authors.affiliation: Service Immunology, Scientific Institute of Public Health (WIV-ISP, Site Ukkel), Brussels, Belgium.
authors.forename: Dorsaf
authors.initials: D
authors.lastname: Hedhli
authors.forename: Olivier
authors.initials: O
authors.lastname: Denis
authors.forename: Daniel
authors.initials: D
authors.lastname: Barkan
authors.forename: Mamadou
authors.initials: M
authors.lastname: Daffé
authors.forename: Michael S
authors.initials: MS
authors.lastname: Glickman
authors.forename: Kris
authors.initials: K
authors.lastname: Huygen
mesh_terms: D000818:Animals; D001500:BCG Vaccine / Q000276:immunology*; D058491:Bacterial Load; D004195:Disease Models, Animal; D058501:Enzyme-Linked Immunospot Assay; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics*; D009163:Mycobacterium bovis / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D009171:Mycolic Acids / Q000378:metabolism*; D009928:Organ Specificity; D010100:Oxygen / Q000378:metabolism; D013045:Species Specificity; D013154:Spleen / Q000382:microbiology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D014132:Trachea / Q000382:microbiology; D016896:Treatment Outcome; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology; D014611:Vaccination; D014774:Virulence / Q000276:immunology
chemical_list: D001500:BCG Vaccine; D020381:Interleukin-17; D009171:Mycolic Acids; D007371:Interferon-gamma; D010100:Oxygen