The Antimicrobial Peptide Cathelicidin Protects Mice from Escherichia coli O157:H7-Mediated Disease

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.

Early Terminal Complement Blockade and C6 Deficiency Are Protective in Enterohemorrhagic Escherichia coli–Infected Mice

“…Baboons injected with Stx have been reported to be an appropriate model (50), but they could not reproduce complement activation via the terminal pathway (51). The mouse model is appropriate for the study of certain aspects of EHECinduced colonic and renal damage (5,12,18), low RBC counts and platelets (7,15), as well as toxin-induced complement activation in the kidney (16). Certain mouse strains, however, have a lower capacity to activate complement (52).…”

“…Animal experiments were performed as previously described (18,39). Mice were treated with streptomycin (5 g/l) in drinking water for 24 h before inoculation and throughout the experiment to reduce the normal flora.…”

“…A previously described mouse model of E. coli O157:H7 infection (12,18,39) was used to test the effect of complement inhibition or deficiency. BALB/c mice were used to test the effect of anti-C5 Ab, and C57BL/6 mice (wild-type and C6-deficient) were used to test the effect of C6 deficiency.…”

“…The renal lesion in HUS patients consists of thrombi in glomerular capillaries, swelling and detachment of endothelial cells from the basement membrane (14), and extensive tubular injury (4,12). Mouse models of EHEC infection or Stx injection reproduce certain aspects of this lesion with platelet deposition in glomeruli (15,16), damaged glomerular capillaries (17), and pronounced tubular damage (7,18). In addition to severe renal damage, 20-50% of patients with HUS develop neurologic manifestations ranging from mild symptoms to coma and stroke and affecting various regions of the brain (19,20).…”

Importance of Endosomal Cathelicidin Degradation To Enhance DNA-Induced Chicken Macrophage Activation

“…They are known for their broad-spectrum antimicrobial activity and their more recently discovered immunomodulatory functions (3). Their importance in innate host defense has been clearly demonstrated in several in vivo knockout models, where loss of HDP expression was shown to result in an increased susceptibility to infections (4)(5)(6). In addition, administration of HDPs was shown to have a protective effect in multiple in vivo infection models (7)(8)(9).…”