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Natural mutations in the sensor kinase of the PhoPR two-component regulatory system modulate virulence of ancestor-like tuberculosis bacilli. | LitMetric

AI Article Synopsis

  • The study investigates the genetic differences between Mycobacterium tuberculosis (MTB) and its ancestor, Mycobacterium canettii, focusing on the PhoPR regulatory system that influences virulence.
  • Mutations in the phoR gene of M. canettii affect PhoP expression and pathogenicity, with the most attenuated strain (STB-K) showing lower expression of PhoP-regulated genes compared to MTB.
  • Gene swapping experiments reveal that the MTB phoPR allele enhances virulence traits in M. canettii, indicating that variations in PhoR have played a role in the evolution of MTB’s increased pathogenicity and ability to persist in hosts.

Article Abstract

The molecular factors and genetic adaptations that contributed to the emergence of Mycobacterium tuberculosis (MTB) from an environmental Mycobacterium canettii-like ancestor, remain poorly investigated. In MTB, the PhoPR two-component regulatory system controls production and secretion of proteins and lipid virulence effectors. Here, we describe that several mutations, present in phoR of M. canettii relative to MTB, impact the expression of the PhoP regulon and the pathogenicity of the strains. First, we establish a molecular model of PhoR and show that some substitutions found in PhoR of M. canettii are likely to impact the structure and activity of this protein. Second, we show that STB-K, the most attenuated available M. canettii strain, displays lower expression of PhoP-induced genes than MTB. Third, we demonstrate that genetic swapping of the phoPR allele from STB-K with the ortholog from MTB H37Rv enhances expression of PhoP-controlled functions and the capacities of the recombinant strain to colonize human macrophages, the MTB target cells, as well as to cause disease in several mouse infection models. Fourth, we extended these observations to other M. canettii strains and confirm that PhoP-controlled functions are expressed at lower levels in most M. canettii strains than in M. tuberculosis. Our findings suggest that distinct PhoR variants have been selected during the evolution of tuberculosis bacilli, contributing to higher pathogenicity and persistence of MTB in the mammalian host.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10348564PMC
http://dx.doi.org/10.1371/journal.ppat.1011437DOI Listing

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