In contrast to the great majority of mycobacterial species that are harmless saprophytes, Mycobacterium tuberculosis and other closely related members of the M. tuberculosis complex (MTBC) have evolved to be among the deadliest human and animal pathogens. While M. tuberculosis strains are globally dispersed and belong to several independent strain lineages (L1-L4, L7), the animal-adapted members (M. bovis, M. pinnipedii, M. microti, M. orygis etc.) form a subgroup in the MTBC phylogenetic tree, which clusters with M. africanum strains that represent two main clades of human tubercle bacilli (L5, L6) in West Africa. Intriguingly, all these members of the MTBC with different host adaptations show very high similarity at the genome level, with only up to 2500 SNPs for the most distant strains. In contrast, Mycobacterium canettii strains that can also cause human tuberculosis and exhibit unusual smooth colony morphology due to production of lipooligosaccharides (LOS), show a much greater genetic diversity (16000-60000 SNPs) and thereby most likely represent the progenitor pool from which the MTBC has evolved and clonally expanded. Comparisons can now identify traits that have contributed to the outstanding evolutionary success of M. tuberculosis as a human pathogen.
Apart from genomic regions that differ, we also found regions that were highly conserved among the different groups. One of these regions was the genomic locus encoding the ESX-1/type VII secretion system. This system, which is absent from the attenuated BCG and Mycobacterium microti vaccine strains is involved in the rupture of the phagolysosomal membrane in host cells causing subsequent innate signalling events. The presence of ESX-1 or its absence from certain mycobacterial strains or strain-lineages thus strongly influences the virulence potential and the immunological properties of a given strain. This knowledge is of importance for the construction of recombinant BCG vaccines with increased protective potential, such as the recently developed BCG::ESX-1mar strain that heterologously expresses the ESX-1 system from Mycobacterium marinum and provides virulence-neutral enhancement of immunogenicity and protection.