doi:10.1073/pnas.1406693111engGonzalo-Asensio, J.Malaga, W.Pawlik, A.Astarie-Dequeker, C.Passemar, C.Moreau, F.Laval, F.Daffé, M.Martin, C.Brosch, R.Guilhot, C.Evolutionary history of tuberculosis shaped by conserved mutations in the PhoPR virulence regulatorART-2014-87719Although the bovine tuberculosis (TB) agent, Mycobacterium bovis, may infect humans and cause disease, long-term epidemiological data indicate that humans represent a spill-over host in which infection with M. bovis is not self-maintaining. Indeed, human-to-human transmission of M. bovis strains and other members of the animal lineage of the tubercle bacilli is very rare. Here, we report on three mutations affecting the two-component virulence regulation system PhoP/PhoR (PhoPR) in M. bovis and in the closely linked Mycobacterium africanum lineage 6 (L6) that likely account for this discrepancy. Genetic transfer of these mutations into the human TB agent, Mycobacterium tuberculosis, resulted in down-regulation of the PhoP regulon, with loss of biologically active lipids, reduced secretion of the 6-kDa early antigenic target (ESAT-6), and lower virulence. Remarkably, the deleterious effects of the phoPR mutations were partly compensated by a deletion, specific to the animal-adapted and M. africanum L6 lineages, that restores ESAT-6 secretion by a PhoPR-independent mechanism. Similarly, we also observed that insertion of an IS6110 element upstream of the phoPR locus may completely revert the phoPR-bovis–associated fitness loss, which is the case for an exceptional M. bovis human outbreak strain from Spain. Our findings ultimately explain the long-term epidemiological data, suggesting that M. bovis and related phoPR-mutated strains pose a lower risk for progression to overt human TB, with major impact on the evolutionary history of TB.2014http://zaguan.unizar.es/record/6088710.1073/pnas.1406693111http://zaguan.unizar.es/record/60887oai:zaguan.unizar.es:60887info:eu-repo/grantAgreement/ES/MINECO/BIO2011-23555info:eu-repo/grantAgreement/ES/MICINN/Juan de la Cierva Program-JCI-2009-03799info:eu-repo/grantAgreement/EC/FP7/260872/EU/More Medicines for Tuberculosis/MM4TBinfo:eu-repo/grantAgreement/EC/FP7/241745/EU/Discovery and preclinical development of new generation tuberculosis vaccines/NEWTBVACinfo:eu-repo/grantAgreement/ES/FIS/FIS12/1970info:eu-repo/grantAgreement/ES/FEDER/POCTEFA-REFBIO-EFA237-11Proceedings of the National Academy of Sciences 111, 31 (2014), 11491-11496byhttp://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccess