Epigenetic regulation of the nitrosative stress response and intracellular macrophage survival by extraintestinal pathogenic Escherichia coli

Mol Microbiol. 2012 Mar;83(5):908-25. doi: 10.1111/j.1365-2958.2012.07977.x. Epub 2012 Jan 30.


Extraintestinal pathogenic Escherichia coli (ExPEC) reside in the enteric tract as a commensal reservoir, but can transition to a pathogenic state by invading normally sterile niches, establishing infection and disseminating to invasive sites like the bloodstream. Macrophages are required for ExPEC dissemination, suggesting the pathogen has developed mechanisms to persist within professional phagocytes. Here, we report that FimX, an ExPEC-associated DNA invertase that regulates the major virulence factor type 1 pili (T1P), is also an epigenetic regulator of a LuxR-like response regulator HyxR. FimX regulated hyxR expression through bidirectional phase inversion of its promoter region at sites different from the type 1 pili promoter and independent of integration host factor (IHF). In vitro, transition from high to low HyxR expression produced enhanced tolerance of reactive nitrogen intermediates (RNIs), primarily through de-repression of hmpA, encoding a nitric oxide-detoxifying flavohaemoglobin. However, in the macrophage, HyxR produced large effects on intracellular survival in the presence and absence of RNI and independent of Hmp. Collectively, we have shown that the ability of ExPEC to survive in macrophages is contingent upon the proper transition from high to low HyxR expression through epigenetic regulatory control by FimX.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • DNA, Bacterial / genetics
  • Epigenesis, Genetic*
  • Escherichia coli / genetics*
  • Escherichia coli / metabolism*
  • Escherichia coli / pathogenicity
  • Escherichia coli Proteins / genetics
  • Escherichia coli Proteins / metabolism*
  • Fimbriae Proteins / metabolism
  • Gene Expression Regulation, Bacterial
  • Macrophages / microbiology*
  • Mice
  • Promoter Regions, Genetic
  • Reactive Nitrogen Species / metabolism*
  • Sequence Deletion
  • Sequence Inversion
  • Virulence Factors / metabolism


  • DNA, Bacterial
  • Escherichia coli Proteins
  • Reactive Nitrogen Species
  • Virulence Factors
  • Fimbriae Proteins