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

Proc Natl Acad Sci U S A. 2014 Aug 5;111(31):11491-6. doi: 10.1073/pnas.1406693111. Epub 2014 Jul 21.

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.

Keywords: adaptation; evolution; phylogeny; zoonosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Antigens, Bacterial
  • Bacterial Proteins / genetics*
  • Bacterial Proteins / metabolism
  • Biological Evolution*
  • Cattle
  • Conserved Sequence / genetics
  • Gene Deletion
  • Host-Pathogen Interactions
  • Humans
  • Mutagenesis, Insertional
  • Mutation / genetics*
  • Mycobacterium / genetics
  • Mycobacterium bovis / genetics
  • Mycobacterium bovis / pathogenicity
  • Mycobacterium tuberculosis / genetics*
  • Mycobacterium tuberculosis / pathogenicity*
  • Phylogeny
  • Polymorphism, Single Nucleotide / genetics
  • Tuberculosis / genetics
  • Tuberculosis / microbiology*
  • Virulence / genetics

Substances

  • Antigens, Bacterial
  • Bacterial Proteins
  • ESAT-6 protein, Mycobacterium tuberculosis
  • PhoR protein, Bacteria
  • PhoP protein, Bacteria

Associated data

  • GEO/GSE54421
  • GEO/GSM1314812
  • GEO/GSM1314813
  • GEO/GSM1314814
  • GEO/GSM1314815
  • GEO/GSM1314816
  • GEO/GSM1314817
  • GEO/GSM1314818
  • GEO/GSM1314819