The Path physiology of Renal Failure in a Shiga Toxin plus Lipopolysaccharide Induced Murine Model of Hemolytic Uremic Syndrome

Author:
Psotka, Mitchell Adam, Department of Microbiology, University of Virginia
Advisors:
Obrig, Tom, Department of Microbiology, University of Virginia
Bouton, Amy, Department of Microbiology, University of Virginia
Bender, Tim, Department of Microbiology, University of Virginia
Blackman, Brett, Department of Biomed Engineering, University of Virginia
Fox, Jay, Department of Microbiology, University of Virginia
Abstract:

Hemolytic uremic syndrome (HUS) is the primary cause of worldwide pediatric acute renal failure. The vast majority of HUS is due to gastrointestinal infection with Shiga toxin producing Escherichia coli (STEC), bacteria that produce the ribosomal protein synthesis inhibitor Shiga toxin (Stx). During the diarrheal prodrome, virulence factors lipopolysaccharide (LPS) and Stx cross into the systemic circulation and cause inflammation and apoptosis in many tissues. The multi-organ pathology that results from toxemia consists of microvascular thrombosis and tissue ischemia with parenchymal destruction. The clinical syndrome of HUS typically comprises microangiopathic hemolytic anemia, thrombocytopenia, acute renal failure, a complex inflammatory response, and neurologic dysfunction. The prognosis is variable; however death or significant lasting renal impairment occurs in up to half of cases. Current treatment consists only of supportive care with intravenous fluids and dialysis, and therapeutic advances have been unforthcoming. Due to the infrequent and sporadic nature of HUS, clinical and therapeutic advancement require an appropriate model system that will allow the underlying mechanisms of this disease to be elucidated. Thus far, only expensive and cumbersome large animal models mimic the human disease, and small animal models of HUS are either incomplete or inadequate. This work fully describes the renal failure that occurs in the mouse model of Shiga toxin mediated HUS. Intraperitoneal injection of Shiga toxin 2 (Stx2) plus LPS into mice causes systemic toxemia and results in death over 96 hours. Acute renal failure, thrombocytopenia, inflammation and neurologic dysfunction develop as well. Nevertheless, although many of the findings correspond with human disease, iii the etiology of Shiga toxin induced renal failure in the mouse is distinct from that in humans. Human renal glomerular and tubular cell types are rich in Gb 3 , while the mouse only produces Gb 3 in renal tubular cells. For this reason, Stx causes only tubular dysfunction in the mouse, and the renal failure is not due to microvascular thrombosis. Therefore, although the mouse model provides a means to evaluate therapeutics that block Shiga toxin mediated cellular toxicity, it does not appropriately recapitulate human HUS.

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Degree:
PHD (Doctor of Philosophy)
Language:
English
Rights:
All rights reserved (no additional license for public reuse)
Issued Date:
2008/08/01