Interplay between enterobactin, myeloperoxidase and lipocalin 2 regulates E. coli survival in the inflamed gut

Nat Commun. 2015 May 12;6:7113. doi: 10.1038/ncomms8113.

Abstract

During an inflammatory response in the gut, some commensal bacteria such as E. coli can thrive and contribute to disease. Here we demonstrate that enterobactin (Ent), a catecholate siderophore released by E. coli, is a potent inhibitor of myeloperoxidase (MPO), a bactericidal enzyme of the host. Glycosylated Ent (salmochelin) and non-catecholate siderophores (yersiniabactin and ferrichrome) fail to inhibit MPO activity. An E. coli mutant (ΔfepA) that overproduces Ent, but not an Ent-deficient double mutant (ΔaroB/ΔfepA), inhibits MPO activity and exhibits enhanced survival in inflamed guts. This survival advantage is counter-regulated by lipocalin 2, a siderophore-binding host protein, which rescues MPO from Ent-mediated inhibition. Spectral analysis reveals that Ent interferes with compound I [oxoiron, Fe(IV)=O] and reverts the enzyme back to its native ferric [Fe(III)] state. These findings define a fundamental mechanism by which E. coli surpasses the host innate immune responses during inflammatory gut diseases and gains a distinct survival advantage.

Publication types

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

MeSH terms

  • Acute-Phase Proteins / genetics
  • Acute-Phase Proteins / metabolism*
  • Animals
  • Colitis / chemically induced
  • Dextran Sulfate / toxicity
  • Enterobactin / genetics
  • Enterobactin / metabolism*
  • Escherichia coli / physiology*
  • Female
  • Gene Expression Regulation
  • Inflammation / chemically induced*
  • Inflammation / microbiology
  • Lipocalin-2
  • Lipocalins / genetics
  • Lipocalins / metabolism*
  • Mice, Inbred BALB C
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Peroxidase / antagonists & inhibitors
  • Peroxidase / genetics
  • Peroxidase / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*

Substances

  • Acute-Phase Proteins
  • LCN2 protein, human
  • Lipocalin-2
  • Lipocalins
  • Oncogene Proteins
  • Proto-Oncogene Proteins
  • Lcn2 protein, mouse
  • Enterobactin
  • Dextran Sulfate
  • Peroxidase