60887 20190529115220.0 doi 10.1073/pnas.1406693111 sideral 87719 ART-2014-87719 eng Gonzalo-Asensio, J. Evolutionary history of tuberculosis shaped by conserved mutations in the PhoPR virulence regulator 2014 Access copy available to the general public Unrestricted Although 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. info:eu-repo/grantAgreement/ES/MINECO/BIO2011-23555 info:eu-repo/grantAgreement/ES/MICINN/Juan de la Cierva Program-JCI-2009-03799 info:eu-repo/grantAgreement/EC/FP7/260872/EU/More Medicines for Tuberculosis/MM4TB info:eu-repo/grantAgreement/EC/FP7/241745/EU/Discovery and preclinical development of new generation tuberculosis vaccines/NEWTBVAC info:eu-repo/grantAgreement/ES/FIS/FIS12/1970 info:eu-repo/grantAgreement/ES/FEDER/POCTEFA-REFBIO-EFA237-11 info:eu-repo/semantics/openAccess by http://creativecommons.org/licenses/by/3.0/es/ 9.674 2014 MULTIDISCIPLINARY SCIENCES 4 / 57 = 0.07 2014 Q1 T1 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Malaga, W. Pawlik, A. Astarie-Dequeker, C. Passemar, C. Moreau, F. Laval, F. Daffé, M. (orcid)0000-0003-2993-5478 Martin, C. Universidad de Zaragoza Brosch, R. Guilhot, C. 1008 630 Universidad de Zaragoza Dpto. Microb.Med.Pr.,Sal.Públ. Área Microbiología 111, 31 (2014), 11491-11496 Proc. Natl. Acad. Sci. Proceedings of the National Academy of Sciences 0027-8424 1330012 http://zaguan.unizar.es/record/60887/files/texto_completo.pdf Versión publicada 147218 http://zaguan.unizar.es/record/60887/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:60887 articulos driver 2019-05-29-11:41:45 ARTICLE