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

Abstract : 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.
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Submitted on : Tuesday, October 22, 2019 - 1:15:52 PM
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J. Gonzalo-Asensio, W. Malaga, Alexandre Pawlik, Catherine Astarie-Dequeker, C. Passemar, et al.. Evolutionary history of tuberculosis shaped by conserved mutations in the PhoPR virulence regulator. Proceedings of the National Academy of Sciences of the United States of America , National Academy of Sciences, 2014, 111 (31), pp.11491-11496. ⟨10.1073/pnas.1406693111⟩. ⟨hal-02325922⟩



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