Genome plasticity of BCG and impact on vaccine efficacy.
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.
Brosch
Roland
R
Unité de Génétique Moléculaire Bactérienne, Institut Pasteur, 28 Rue du Docteur Roux, 75724 Paris Cedex 15, France.
Gordon
Stephen V
SV
Garnier
Thierry
T
Eiglmeier
Karin
K
Frigui
Wafa
W
Valenti
Philippe
P
Dos Santos
Sandrine
S
Duthoy
Stéphanie
S
Lacroix
Céline
C
Garcia-Pelayo
Carmen
C
Inwald
Jacqueline K
JK
Golby
Paul
P
Garcia
Javier Nuñez
JN
Hewinson
R Glyn
RG
Behr
Marcel A
MA
Quail
Michael A
MA
Churcher
Carol
C
Barrell
Bart G
BG
Parkhill
Julian
J
Cole
Stewart T
ST
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
D001500:BCG Vaccine; D012333:RNA, Messenger; D032581:Tuberculosis Vaccines