A Single Amino Acid Change in the Response Regulator PhoP, Acquired duringYersinia pestisEvolution, Affects PhoP Target Gene Transcription and Polymyxin B Susceptibility Academic Article uri icon

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  • ABSTRACTYersinia pestis, the causative agent of plague, evolved from the closely related pathogenYersinia pseudotuberculosis. During its emergence,Y. pestisis believed to have acquired its unique pathogenic characteristics through numerous gene gains/losses, genomic rearrangements, and single nucleotide polymorphism (SNP) changes. One such SNP creates a single amino acid variation in the DNA binding domain of PhoP, the response regulator in the PhoP/PhoQ two-component system.Y. pseudotuberculosisand the basal human-avirulent strains ofY. pestisharbor glycines at position 215 of PhoP, whereas the modern human-virulent strains (e.g., KIM and CO92) harbor serines at this residue. Since PhoP plays multiple roles in the adaptation ofY. pestisto stressful host conditions, we tested whether this amino acid substitution affects PhoP activity or the ability ofY. pestisto survive in host environments. Compared to the parental KIM6+ strain carrying the modern allele ofphoP(phoP-S215), a derivative carrying the basal allele (phoP-G215) exhibited slightly defective growth under a low-Mg2+condition and decreased transcription of a PhoP target gene,ugd, as well as an ∼8-fold increase in the susceptibility to the antimicrobial peptide polymyxin B. ThephoP-G215strain showed no apparent defect in flea colonization, although aphoP-null mutant showed decreased flea infectivity in competition experiments. Our results suggest that the amino acid variation at position 215 of PhoP causes subtle changes in the PhoP activity and raise the possibility that the change in this residue have contributed to the evolution of increased virulence inY. pestis.IMPORTANCEY. pestisacquired a single nucleotide polymorphism (SNP) inphoPwhen the highly human-virulent strains diverged from less virulent basal strains, resulting in an amino acid substitution in the DNA binding domain of the PhoP response regulator. We show thatY. pestiscarrying the modernphoPallele has an increased ability to induce the PhoP-regulatedugdgene and resist antimicrobial peptides compared to an isogenic strain carrying the basal allele. Given the important roles PhoP plays in host adaptation, the results raise an intriguing possibility that this amino acid substitution contributed to the evolution of increased virulence inY. pestis. Additionally, we present the first evidence thatphoPconfers a survival fitness advantage toY. pestisinside the flea midgut.


  • Fukuto, Hana S
  • Vadyvaloo, Viveka
  • McPhee, Joseph B
  • Poinar, Hendrik
  • Holmes, Edward C
  • Bliska, James B

publication date

  • February 12, 2018