Abstract
BackgroundStudies of Mycobacterium bovis BCG strains used in different countries and vaccination programs show clear variations in the genomes and immune protective properties of BCG strains. The aim of this study was to characterise the genomic and immune proteomic profile of the BCG 1931 strain used in Mexico.ResultsBCG Mexico 1931 has a circular chromosome of 4,350,386 bp with a G+C content and numbers of genes and pseudogenes similar to those of BCG Tokyo and BCG Pasteur. BCG Mexico 1931 lacks Region of Difference 1 (RD1), RD2 and N-RD18 and one copy of IS6110, indicating that BCG Mexico 1931 belongs to DU2 group IV within the BCG vaccine genealogy. In addition, this strain contains three new RDs, which are 53 (RDMex01), 655 (RDMex02) and 2,847 bp (REDMex03) long, and 55 single-nucleotide polymorphisms representing non-synonymous mutations compared to BCG Pasteur and BCG Tokyo. In a comparative proteomic analysis, the BCG Mexico 1931, Danish, Phipps and Tokyo strains showed 812, 794, 791 and 701 protein spots, respectively. The same analysis showed that BCG Mexico 1931 shares 62% of its protein spots with the BCG Danish strain, 61% with the BCG Phipps strain and only 48% with the BCG Tokyo strain. Thirty-nine reactive spots were detected in BCG Mexico 1931 using sera from subjects with active tuberculosis infections and positive tuberculin skin tests.ConclusionsBCG Mexico 1931 has a smaller genome than the BCG Pasteur and BCG Tokyo strains. Two specific deletions in BCG Mexico 1931 are described (RDMex02 and RDMex03). The loss of RDMex02 (fadD23) is associated with enhanced macrophage binding and RDMex03 contains genes that may be involved in regulatory pathways. We also describe new antigenic proteins for the first time.
Highlights
Studies of Mycobacterium bovis Bacillus CalmetteGuérin (BCG) strains used in different countries and vaccination programs show clear variations in the genomes and immune protective properties of BCG strains
The absence of the region of difference (RD) Danish/Glaxo region, which is specific to BCG Danish, in BCG Mexico 1988 and 1997 confirms this result and is consistent with historical records indicating that BCG vaccine production in Mexico utilised the BCG Danish 1331 strain beginning in 1970
The amplification pattern of DU regions in BCG Mexico 1931 indicated duplication of DU2-IV, in contrast to those of BCG Mexico 1988 and BCG Mexico 1997, which showed duplication of DU2-III (Table 1). These differences in RDs and DUs confirm that BCG Mexico 1931 is a different strain from BCG Mexico 1988 and 1997, which are related to BCG Danish
Summary
Studies of Mycobacterium bovis BCG strains used in different countries and vaccination programs show clear variations in the genomes and immune protective properties of BCG strains. Use of BCG in the early 1920s proved effective in protecting against TB, leading to distribution of the vaccine in many countries. It has been shown that deletion of this region in M. tuberculosis H37Rv leads to attenuation of the strain [14]; complementation of BCG Pasteur with RD1 does not fully restore virulence to wild-type levels [15]. Kozak et al reported that BCG Pasteur, a strain that lacks RD2, exhibits decreased immunogenicity compared to BCG Russia, a strain that has retained RD2 [16]. These two strains show no difference in their level of protection against pulmonary tuberculosis. The differences observed among BCG strains suggest that additional attenuating mutations may be involved in the attenuation of individual BCG strains
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