title: Genome plasticity of BCG and impact on vaccine efficacy.
abstract: To understand the evolution, attenuation, and variable protective efficacy of bacillus Calmette-Guérin (BCG) vaccines, Mycobacterium bovis BCG Pasteur 1173P2 has been subjected to comparative genome and transcriptome analysis. The 4,374,522-bp genome contains 3,954 protein-coding genes, 58 of which are present in two copies as a result of two independent tandem duplications, DU1 and DU2. DU1 is restricted to BCG Pasteur, although four forms of DU2 exist; DU2-I is confined to early BCG vaccines, like BCG Japan, whereas DU2-III and DU2-IV occur in the late vaccines. The glycerol-3-phosphate dehydrogenase gene, glpD2, is one of only three genes common to all four DU2 variants, implying that BCG requires higher levels of this enzyme to grow on glycerol. Further amplification of the DU2 region is ongoing, even within vaccine preparations used to immunize humans. An evolutionary scheme for BCG vaccines was established by analyzing DU2 and other markers. Lesions in genes encoding sigma-factors and pleiotropic transcriptional regulators, like PhoR and Crp, were also uncovered in various BCG strains; together with gene amplification, these affect gene expression levels, immunogenicity, and, possibly, protection against tuberculosis. Furthermore, the combined findings suggest that early BCG vaccines may even be superior to the later ones that are more widely used.
authors: Unité de Génétique Moléculaire Bactérienne, Institut Pasteur, 28 Rue du Docteur Roux, 75724 Paris Cedex 15, France.
authors: Roland
authors: R
authors: Brosch
authors: Stephen V
authors: SV
authors: Gordon
authors: Thierry
authors: T
authors: Garnier
authors: Karin
authors: K
authors: Eiglmeier
authors: Wafa
authors: W
authors: Frigui
authors: Philippe
authors: P
authors: Valenti
authors: Sandrine
authors: S
authors: Dos Santos
authors: Stéphanie
authors: S
authors: Duthoy
authors: Céline
authors: C
authors: Lacroix
authors: Carmen
authors: C
authors: Garcia-Pelayo
authors: Jacqueline K
authors: JK
authors: Inwald
authors: Paul
authors: P
authors: Golby
authors: Javier Nuñez
authors: JN
authors: Garcia
authors: R Glyn
authors: RG
authors: Hewinson
authors: Marcel A
authors: MA
authors: Behr
authors: Michael A
authors: MA
authors: Quail
authors: Carol
authors: C
authors: Churcher
authors: Bart G
authors: BG
authors: Barrell
authors: Julian
authors: J
authors: Parkhill
authors: Stewart T
authors: ST
authors: Cole
mesh_terms: D001500:BCG Vaccine / Q000235:genetics*; D019143:Evolution, Molecular; D016678:Genome; D016680:Genome, Bacterial; D023281:Genomics; D006801:Humans; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009163:Mycobacterium bovis / Q000235:genetics / Q000276:immunology*; D010641:Phenotype; D010802:Phylogeny; D012333:RNA, Messenger / Q000378:metabolism; D014376:Tuberculosis / Q000276:immunology / Q000382:microbiology* / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000235:genetics
chemical_list: D001500:BCG Vaccine; D012333:RNA, Messenger; D032581:Tuberculosis Vaccines