title: Loss of Lipid Virulence Factors Reduces the Efficacy of the BCG Vaccine.
abstract: Bacille Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis, is the only vaccine available for tuberculosis (TB) control. BCG comprises a number of substrains that exhibit genetic and biochemical differences. Whether and how these differences affect BCG efficacy remain unknown. Compared to other BCG strains, BCG-Japan, -Moreau, and -Glaxo are defective in the production of phthiocerol dimycocerosates (PDIMs) and phenolic glycolipids (PGLs), two lipid virulence factors. To determine if the loss of PDIMs/PGLs affects BCG efficacy, we constructed a PDIM/PGL-deficient strain of BCG-Pasteur by deleting fadD28, and compared virulence, immunogenicity, and protective efficacy in animal models. SCID mouse infection experiments showed that ∆fadD28 was more attenuated than wild type (WT). The ∆fadD28 and WT strains induced equivalent levels of antigen specific IFN-γ by CD4(+) and CD8(+) T cells; however, ∆fadD28 was less effective against Mycobacterium tuberculosis challenge in both BALB/c mice and guinea pigs. These results indicate that the loss of PIDMs/PGLs reduces the virulence and protective efficacy of BCG. Since the loss of PDIMs/PGLs occurs naturally in a subset of BCG strains, it also suggests that these strains may have been over-attenuated, which compromises their effectiveness. Our finding has important implications for current BCG programs and future vaccine development.
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Tran
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: Sang Kyun
authors.initials: SK
authors.lastname: Ahn
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Ng
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D001500:BCG Vaccine / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019730:Carbon-Sulfur Ligases / Q000235:genetics* / Q000276:immunology; D006017:Glycolipids / Q000235:genetics* / Q000276:immunology; D006168:Guinea Pigs; D006801:Humans; D007564:Japan; D008055:Lipids / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000472:pathogenicity; D014376:Tuberculosis / Q000235:genetics* / Q000276:immunology / Q000517:prevention & control; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology
chemical_list: D001500:BCG Vaccine; D006017:Glycolipids; D008055:Lipids; D037521:Virulence Factors; C008901:phthiocerol dimycocerosate; D019730:Carbon-Sulfur Ligases; C510957:FadD28 protein, Mycobacterium tuberculosis