000060887 001__ 60887
000060887 005__ 20190529115220.0
000060887 0247_ $$2doi$$a10.1073/pnas.1406693111
000060887 0248_ $$2sideral$$a87719
000060887 037__ $$aART-2014-87719
000060887 041__ $$aeng
000060887 100__ $$aGonzalo-Asensio, J.
000060887 245__ $$aEvolutionary history of tuberculosis shaped by conserved mutations in the PhoPR virulence regulator
000060887 260__ $$c2014
000060887 5060_ $$aAccess copy available to the general public$$fUnrestricted
000060887 5203_ $$aAlthough 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.
000060887 536__ $$9info:eu-repo/grantAgreement/ES/MINECO/BIO2011-23555$$9info:eu-repo/grantAgreement/ES/MICINN/Juan de la Cierva Program-JCI-2009-03799$$9info:eu-repo/grantAgreement/EC/FP7/260872/EU/More Medicines for Tuberculosis/MM4TB$$9info:eu-repo/grantAgreement/EC/FP7/241745/EU/Discovery and preclinical development of new generation tuberculosis vaccines/NEWTBVAC$$9info:eu-repo/grantAgreement/ES/FIS/FIS12/1970$$9info:eu-repo/grantAgreement/ES/FEDER/POCTEFA-REFBIO-EFA237-11
000060887 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000060887 590__ $$a9.674$$b2014
000060887 591__ $$aMULTIDISCIPLINARY SCIENCES$$b4 / 57 = 0.07$$c2014$$dQ1$$eT1
000060887 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000060887 700__ $$aMalaga, W.
000060887 700__ $$aPawlik, A.
000060887 700__ $$aAstarie-Dequeker, C.
000060887 700__ $$aPassemar, C.
000060887 700__ $$aMoreau, F.
000060887 700__ $$aLaval, F.
000060887 700__ $$aDaffé, M.
000060887 700__ $$0(orcid)0000-0003-2993-5478$$aMartin, C.$$uUniversidad de Zaragoza
000060887 700__ $$aBrosch, R.
000060887 700__ $$aGuilhot, C.
000060887 7102_ $$11008$$2630$$aUniversidad de Zaragoza$$bDpto. Microb.Med.Pr.,Sal.Públ.$$cÁrea Microbiología
000060887 773__ $$g111, 31 (2014), 11491-11496$$pProc. Natl. Acad. Sci.$$tProceedings of the National Academy of Sciences$$x0027-8424
000060887 8564_ $$s1330012$$uhttps://zaguan.unizar.es/record/60887/files/texto_completo.pdf$$yVersión publicada
000060887 8564_ $$s147218$$uhttps://zaguan.unizar.es/record/60887/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000060887 909CO $$ooai:zaguan.unizar.es:60887$$particulos$$pdriver
000060887 951__ $$a2019-05-29-11:41:45
000060887 980__ $$aARTICLE