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Infection and Immunity, October 2008, p. 4469-4478, Vol. 76, No. 10
0019-9567/08/$08.00+0     doi:10.1128/IAI.00592-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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

Kristin A. D. Sauter,1 Angela R. Melton-Celsa,2 Kay Larkin,3 Megan L. Troxell,3 Alison D. O'Brien,2 and Bruce E. Magun1*

Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon 97239,1 Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814,2 Department of Pathology, Oregon Health and Science University, Portland, Oregon 972393

Received 14 May 2008/ Returned for modification 16 June 2008/ Accepted 25 July 2008

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.

* Corresponding author. Mailing address: Department of Cell and Developmental Biology, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239. Phone: (503) 494-7811. Fax: (503) 494-4253. E-mail: magunb{at}ohsu.edu

{triangledown} Published ahead of print on 11 August 2008.

Editor: B. A. McCormick

Infection and Immunity, October 2008, p. 4469-4478, Vol. 76, No. 10
0019-9567/08/$08.00+0     doi:10.1128/IAI.00592-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Bitzan, M., Poole, R., Mehran, M., Sicard, E., Brockus, C., Thuning-Roberson, C., Riviere, M. (2009). Safety and Pharmacokinetics of Chimeric Anti-Shiga Toxin 1 and Anti-Shiga Toxin 2 Monoclonal Antibodies in Healthy Volunteers. Antimicrob. Agents Chemother. 53: 3081-3087 [Abstract] [Full Text]  
  • Smith, M. J., Melton-Celsa, A. R., Sinclair, J. F., Carvalho, H. M., Robinson, C. M., O'Brien, A. D. (2009). Monoclonal Antibody 11E10, Which Neutralizes Shiga Toxin Type 2 (Stx2), Recognizes Three Regions on the Stx2 A Subunit, Blocks the Enzymatic Action of the Toxin In Vitro, and Alters the Overall Cellular Distribution of the Toxin. Infect. Immun. 77: 2730-2740 [Abstract] [Full Text]  


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