ArticleProceedings of the National Academy of Sciences of the United States of America2014
Evolutionary history of tuberculosis shaped by conserved mutations in the PhoPR virulence regulator.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 100 papers.
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100 citing papers in PubMed, 216 citations in OpenAlex.
- Article
- Different transcriptional regulatory activities of Mycobacterium bovis and Mycobacterium tuberculosis PhoPR systems.Access microbiology · 2026Article
- Evaluating selection at intermediate scales within genes provides robust identification of genes under positive selection in M. tuberculosis clinical isolates.Tuberculosis (Edinburgh, Scotland) · 2025Article
- Article
- Review
- Evaluating selection at intermediate scales within genes provides robust identification of genes under positive selection inbioRxiv : the preprint server for biology · 2025Article
- Article
- Comparative transcriptomic signatures of virulent and attenuatedFrontiers in cellular and infection microbiology · 2025Article
- Marine sponge microbe provides insights into evolution and virulence of the tubercle bacillus.PLoS pathogens · 2024Article
- Live Attenuated Vaccines against Tuberculosis: Targeting the Disruption of Genes Encoding the Secretory Proteins of Mycobacteria.Vaccines · 2024Review
- The antagonistic transcription factors, EspM and EspN, regulate the ESX-1 secretion system inmBio · 2024Article
- Evolution and emergence of Mycobacterium tuberculosis.FEMS microbiology reviews · 2024Review
- Development and evaluation of a triplex droplet digital PCR method for differentiation ofFrontiers in microbiology · 2024Article
- Global-scale GWAS associates a subset of SNPs with animal-adapted variants in M. tuberculosis complex.BMC medical genomics · 2023Article
- Exploring virulence in Mycobacterium bovis: clues from comparative genomics and perspectives for the future.Irish veterinary journal · 2023Review
- Will we ever eradicate animal tuberculosis?Irish veterinary journal · 2023Article
- Natural mutations in the sensor kinase of the PhoPR two-component regulatory system modulate virulence of ancestor-like tuberculosis bacilli.PLoS pathogens · 2023Article
- ESAT-6 a Major Virulence Factor ofBiomolecules · 2023Review
- Genetic Diversity and Population Structure ofPathogens (Basel, Switzerland) · 2023Article
- Infectious and Inflammatory Pathways to Cough.Annual review of physiology · 2023Review
40 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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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