Clinical Escherichia coli isolates utilize alpha-hemolysin to inhibit in vitro epithelial cytokine production

Microbes Infect. 2012 Jul;14(7-8):628-38. doi: 10.1016/j.micinf.2012.01.010. Epub 2012 Jan 25.


Uropathogenic Escherichia coli is the primary cause of urinary tract infections, which affects over 60% of women during their lifetime. UPEC exhibits a number of virulence traits that facilitate colonization of the bladder, including inhibition of cytokine production by bladder epithelial cells. The goal of this study was to identify the mechanism of this inhibition. We observed that cytokine suppression was associated with rapid cytotoxicity toward epithelial cells. We found that cytotoxicity, cytokine suppression and alpha-hemolysin production were all tightly linked in clinical isolates. We screened a UPEC fosmid library and identified clones that gained the cytotoxicity and cytokine-suppression phenotypes. Both clones contained fosmids encoding a PAI II(J96)-like domain and expressed the alpha-hemolysin (hlyA) encoded therein. Mutation of the fosmid-encoded hly operon abolished cytotoxicity and cytokine suppression. Similarly, mutation of the chromosomal hlyCABD operon of UPEC isolate F11 also abolished these phenotypes, and they could be restored by introducing the PAI II(J96)-like domain-encoding fosmid. We also examined the role of alpha-hemolysin in cytokine production both in the murine UTI model as well as patient specimens. We conclude that E. coli utilizes alpha-hemolysin to inhibit epithelial cytokine production in vitro. Its contribution to inflammation during infection requires further study.

MeSH terms

  • Animals
  • Clone Cells
  • Cytokines / biosynthesis*
  • Escherichia coli Infections / microbiology*
  • Escherichia coli Proteins / metabolism*
  • Female
  • Genetic Variation
  • Hemolysin Proteins / metabolism*
  • Humans
  • Mice
  • Urinary Tract Infections / microbiology*
  • Uropathogenic Escherichia coli / metabolism*
  • Uropathogenic Escherichia coli / pathogenicity*
  • Virulence / genetics


  • Cytokines
  • Escherichia coli Proteins
  • Hemolysin Proteins
  • Hlya protein, E coli