Mouse Model of Hemolytic-Uremic Syndrome Caused by Endotoxin-Free Shiga Toxin 2 (Stx2) and Protection from Lethal Outcome by Anti-Stx2 Antibody

Hemolytic-uremic syndrome (HUS) results from infection by Shiga toxin (Stx)-producing Escherichia coli and is the most common cause of acute renal failure in children. We have developed a mouse model of HUS by administering endotoxin-free Stx2 in multiple doses over 7 to 8 days. At sacrifice, moribu...

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Bibliographic Details
Published in:Infection and Immunity 2008-10, Vol.76 (10), p.4469-4478
Main Authors: Sauter, Kristin A.D, Melton-Celsa, Angela R, Larkin, Kay, Troxell, Megan L, O'Brien, Alison D, Magun, Bruce E
Format: Article
Language:English
Subjects:
Animals
Antibodies, Bacterial - therapeutic use
Antibodies, Monoclonal - therapeutic use
Antitoxins - therapeutic use
Bacterial Infections
Biological and medical sciences
Blood Urea Nitrogen
Child
Creatinine - blood
Cytokines - blood
Escherichia coli
Fibrinogen - metabolism
Fundamental and applied biological sciences. Psychology
Hemolytic-Uremic Syndrome - chemically induced
Hemolytic-Uremic Syndrome - prevention & control
Humans
Immunohistochemistry
Kidney - pathology
Kidney - ultrastructure
Leukopenia - chemically induced
Mice
Mice, Inbred C57BL
Microbiology
Microscopy, Electron, Transmission
Proteinuria - chemically induced
Shiga Toxin 2 - antagonists & inhibitors
Shiga Toxin 2 - toxicity
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Summary:Hemolytic-uremic syndrome (HUS) results from infection by Shiga toxin (Stx)-producing Escherichia coli and is the most common cause of acute renal failure in children. We have developed a mouse model of HUS by administering endotoxin-free Stx2 in multiple doses over 7 to 8 days. At sacrifice, moribund animals demonstrated signs of HUS: increased blood urea nitrogen and serum creatinine levels, proteinuria, deposition of fibrin(ogen), glomerular endothelial damage, hemolysis, leukocytopenia, and neutrophilia. Increased expression of proinflammatory chemokines and cytokines in the sera of Stx2-treated mice indicated a systemic inflammatory response. Currently, specific therapeutics for HUS are lacking, and therapy for patients is primarily supportive. Mice that received 11E10, a monoclonal anti-Stx2 antibody, 4 days after starting injections of Stx2 recovered fully, displaying normal renal function and normal levels of neutrophils and lymphocytes. In addition, these mice showed decreased fibrin(ogen) deposition and expression of proinflammatory mediators compared to those of Stx2-treated mice in the absence of antibody. These results indicate that, when performed during progression of HUS, passive immunization of mice with anti-Stx2 antibody prevented the lethal effects of Stx2.
ISSN:0019-9567
1098-5522
DOI:10.1128/IAI.00592-08