The antimicrobial peptide cathelicidin protects mice from Escherichia coli O157:H7-mediated disease

PLoS One. 2012;7(10):e46476. doi: 10.1371/journal.pone.0046476. Epub 2012 Oct 15.

Abstract

This study investigated the role of the antimicrobial peptide cathelicidin in Escherichia coli O157:H7 infection and subsequent renal damage. Mouse and human cathelicidin, CRAMP and LL-37, respectively, killed E. coli O157:H7 in vitro. Intestines from healthy wild-type (129/SvJ) and cathelicidin-knock-out (Camp(-/-)) mice were investigated, showing that cathelicidin-deficient mice had a thinner colonic mucus layer compared with wild-type mice. Wild-type (n = 11) and cathelicidin-knock-out (n = 11) mice were inoculated with E. coli O157:H7. Cathelicidin-deficient animals exhibited higher fecal counts of E. coli O157:H7 and bacteria penetrated the mucus forming attaching-and-effacing lesions to a much higher extent than in wild-type animals. Cathelicidin knock-out mice developed symptoms (9/11) as well as anemia, thrombocytopenia and extensive renal tubular damage while all cathelicidin-producing mice remained asymptomatic with normal laboratory findings. When injected with Shiga toxin intraperitoneally, both murine strains developed the same degree of renal tubular damage and clinical disease indicating that differences in sensitivity to infection between the murine strains were related to the initial intestinal response. In conclusion, cathelicidin substantially influenced the antimicrobial barrier in the mouse colon mucosa. Cathelicidin deficiency lead to increased susceptibility to E. coli O157:H7 infection and subsequent renal damage. Administration of cathelicidin or stimulation of endogenous production may prove to be novel treatments for E. coli O157:H7-induced hemolytic uremic syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Infective Agents / pharmacology*
  • Antimicrobial Cationic Peptides / pharmacology*
  • Escherichia coli Infections / prevention & control*
  • Escherichia coli O157 / pathogenicity*
  • Fluorescent Antibody Technique
  • Mice
  • Mice, Knockout
  • Microbial Sensitivity Tests

Substances

  • Anti-Infective Agents
  • Antimicrobial Cationic Peptides
  • CAP18 lipopolysaccharide-binding protein

Grant support

This study was supported by grants from The Swedish Research Council (K2010-65X-14008-10-3 to DK, K2010-77PK-21628-01-1 to MC), The Torsten Söderberg Foundation, Konung Gustaf V:s 80-årsfond, Fanny Ekdahl's Foundation (to DK) and Crown Princess Lovisa's Society for Child Care (to MC and DK), Karolinska Institutet's research foundations, Sällskapet Barnavård foundation and Samariten foundation (to MC, these grants were administered at Karolinska Institutet). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.