M.tuberculosis mutants lacking oxygenated mycolates show increased immunogenicity and protective efficacy as compared to M. bovis BCG vaccine in an experimental mouse model

• Published in: PloS one 2013-10, Vol.8 (10), p.e76442-e76442
• Main Authors: Hedhli, Dorsaf, Denis, Olivier, Barkan, Daniel, Daffé, Mamadou, Glickman, Michael S, Huygen, Kris
• Format: Article
• Language: English
• Subjects: Acids; Activation; Animals; Apoptosis; Autoimmune diseases; Bacillus Calmette-Guerin vaccine; Bacteria; Bacterial Load; BCG; BCG Vaccine - immunology; CD4 antigen; CD8 antigen; Cell walls; Children; Disease Models, Animal; Drug therapy; Enzyme-Linked Immunospot Assay; Experiments; House mouse; Immunogenicity; Immunology; Infection; Infections; Infectious diseases; Injections, Subcutaneous; Interferon; Interferon-gamma - biosynthesis; Interleukin 17; Interleukin 2; Interleukin-17 - biosynthesis; Lungs; Lymph Nodes - immunology; Lymph Nodes - pathology; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; Mutants; Mutation - genetics; Mycobacterium bovis - immunology; Mycobacterium tuberculosis; Mycobacterium tuberculosis - genetics; Mycobacterium tuberculosis - growth & development; Mycobacterium tuberculosis - immunology; Mycobacterium tuberculosis - pathogenicity; Mycolic Acids - metabolism; Organ Specificity; Oxygen - metabolism; Oxygenation; Public health; Species Specificity; Spleen; Spleen - microbiology; Spleen - pathology; T cells; Th1 Cells - immunology; Th17 Cells - immunology; Trachea; Trachea - microbiology; Treatment Outcome; Tuberculosis; Tuberculosis - immunology; Tuberculosis - microbiology; Tuberculosis vaccines; Tumor necrosis factor; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Vaccination; Vaccine development; Vaccines; Veterinary medicine; Virulence - immunology; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0076442

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.