Evolutionary Landscape of the Mycobacterium tuberculosis Complex from the Viewpoint of PhoPR: Implications for Virulence Regulation and Application to Vaccine Development
ABSTRACTDifferent members of theMycobacteriumgenus have evolved to cause tuberculosis in diverse human populations and in a variety of animal species. Our cumulative knowledge of mycobacterial genomes indicates that mutations in the PhoPR two-component virulence system were acquired not only during the natural evolution of mycobacterial species but also duringin vitrosubculture, which has given rise to the attenuated reference strain H37Ra or to different daughter strains ofMycobacterium bovisBCG. PhoPR is a well-known regulator of pathogenic phenotypes, including secretion of the virulence factor ESAT-6, biosynthesis of acyltrehalose-based lipids, and modulation of antigen export, in members of theMycobacterium tuberculosiscomplex (MTBC). Evolutionarily conserved polymorphisms in PhoPR fromMycobacterium africanum,M. bovis, orM. tuberculosisH37Ra result in loss of functional phenotypes. Interestingly, some members of the MTBC have acquired compensatory mutations to counteract these polymorphisms and, probably, to maintain their pathogenic potential. Some of these compensatory mutations include the insertion of the IS6110element upstream fromphoPRin a particularM. bovisstrain that is able to transmit between humans or polymorphisms inM. africanumandM. bovisthat affect the regulatory region of theespACDoperon, allowing PhoPR-independent ESAT-6 secretion. This review highlights the increasing knowledge of the significance of PhoPR in the evolution of the MTBC and its potential application in the construction of new attenuated vaccines based onphoPRinactivation. In this context, the live attenuated vaccine MTBVAC, based on aphoP fadD26deletion mutant ofM. tuberculosis, is the first vaccine of this kind to successfully enter into clinical development, representing a historic milestone in the field of human vaccinology.