Evolutionary history of tuberculosis shaped by conserved mutations in the PhoPR virulence regulator

Gonzalo-Asensio, J. ; Malaga, W. ; Pawlik, A. ; Astarie-Dequeker, C. ; Passemar, C. ; Moreau, F. ; Laval, F. ; Daffé, M. ; Martin, C. (Universidad de Zaragoza) ; Brosch, R. ; Guilhot, C.

Resumen: 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.

Idioma: Inglés

DOI: 10.1073/pnas.1406693111

Año: 2014

Publicado en: Proceedings of the National Academy of Sciences 111, 31 (2014), 11491-11496
ISSN: 0027-8424

Factor impacto JCR: 9.674 (2014)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 4 / 57 = 0.07 (2014) - Q1 - T1

Financiación: info:eu-repo/grantAgreement/ES/FEDER/POCTEFA-REFBIO-EFA237-11
Financiación: info:eu-repo/grantAgreement/ES/FIS/FIS12/1970
Financiación: info:eu-repo/grantAgreement/EC/FP7/241745/EU/Discovery and preclinical development of new generation tuberculosis vaccines/NEWTBVAC
Financiación: info:eu-repo/grantAgreement/EC/FP7/260872/EU/More Medicines for Tuberculosis/MM4TB
Financiación: info:eu-repo/grantAgreement/ES/MICINN/Juan de la Cierva Program-JCI-2009-03799
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BIO2011-23555

Tipo y forma: Article (Published version)

Área (Departamento): Área Microbiología (Dpto. Microb.Med.Pr.,Sal.Públ.)