title: Early Terminal Complement Blockade and C6 Deficiency Are Protective in Enterohemorrhagic Escherichia coli-Infected Mice.
abstract: Complement activation occurs during enterohemorrhagic Escherichia coli (EHEC) infection and may exacerbate renal manifestations. In this study, we show glomerular C5b-9 deposits in the renal biopsy of a child with EHEC-associated hemolytic uremic syndrome. The role of the terminal complement complex, and its blockade as a therapeutic modality, was investigated in a mouse model of E. coli O157:H7 infection. BALB/c mice were treated with monoclonal anti-C5 i.p. on day 3 or 6 after intragastric inoculation and monitored for clinical signs of disease and weight loss for 14 d. All infected untreated mice (15 of 15) or those treated with an irrelevant Ab (8 of 8) developed severe illness. In contrast, only few infected mice treated with anti-C5 on day 3 developed symptoms (three of eight, p < 0.01 compared with mice treated with the irrelevant Ab on day 3) whereas most mice treated with anti-C5 on day 6 developed symptoms (six of eight). C6-deficient C57BL/6 mice were also inoculated with E. coli O157:H7 and only 1 of 14 developed disease, whereas 10 of 16 wild-type mice developed weight loss and severe disease (p < 0.01). Complement activation via the terminal pathway is thus involved in the development of disease in murine EHEC infection. Early blockade of the terminal complement pathway, before the development of symptoms, was largely protective, whereas late blockade was not. Likewise, lack of C6, and thereby deficient terminal complement complex, was protective in murine E. coli O157:H7 infection.
authors.affiliation: Department of Pediatrics, Clinical Sciences Lund, Lund University, 22185 Lund, Sweden;
authors.forename: Ida
authors.initials: I
authors.lastname: Arvidsson
authors.affiliation: Department of Pediatrics, Clinical Sciences Lund, Lund University, 22185 Lund, Sweden;
authors.forename: Johan
authors.identifier: 0000-0003-1673-0684
authors.initials: J
authors.lastname: Rebetz
authors.affiliation: Department of Pediatrics, Clinical Sciences Lund, Lund University, 22185 Lund, Sweden;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Loos
authors.affiliation: Department of Pediatrics, Karolinska University Hospital, 14186 Stockholm, Sweden; and.
authors.forename: Maria
authors.initials: M
authors.lastname: Herthelius
authors.affiliation: Department of Pediatrics, Clinical Sciences Lund, Lund University, 22185 Lund, Sweden;
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Kristoffersson
authors.affiliation: Department of Oncology and Pathology, Clinical Sciences Lund, Lund University, 22185 Lund, Sweden.
authors.forename: Elisabet
authors.identifier: 0000-0002-2708-2443
authors.initials: E
authors.lastname: Englund
authors.affiliation: Department of Pediatrics, Clinical Sciences Lund, Lund University, 22185 Lund, Sweden; Department of Pediatrics, Karolinska University Hospital, 14186 Stockholm, Sweden; and.
authors.forename: Milan
authors.identifier: 0000-0002-8941-057X
authors.initials: M
authors.lastname: Chromek
authors.affiliation: Department of Pediatrics, Clinical Sciences Lund, Lund University, 22185 Lund, Sweden; Diana.Karpman@med.lu.se.
authors.forename: Diana
authors.identifier: 0000-0001-7220-7658
authors.initials: D
authors.lastname: Karpman
mesh_terms: D000818:Animals; D002675:Child, Preschool; D003183:Complement C6 / Q000037:antagonists & inhibitors* / Q000276:immunology; D015938:Complement Membrane Attack Complex / Q000037:antagonists & inhibitors* / Q000276:immunology; D004195:Disease Models, Animal; D054324:Enterohemorrhagic Escherichia coli; D004927:Escherichia coli Infections / Q000276:immunology*; D005260:Female; D006463:Hemolytic-Uremic Syndrome / Q000276:immunology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL
chemical_list: D003183:Complement C6; D015938:Complement Membrane Attack Complex