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Infect. Immun. doi:10.1128/IAI.00255-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

A Streptozocin-Induced Diabetic Mouse Model of Urinary Tract Infection

Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, 63110, United States of America

^* To whom correspondence should be addressed. Email: hultgren{at}borcim.wustl.edu.

	Abstract

Diabetics have a higher incidence of urinary tract infection (UTI), are infected with a broader range of uropathogens, and more commonly develop serious UTI sequelae. To better study UTI in the diabetic host, we created and characterized a murine model of diabetic UTI using the pancreatic islet -cell toxin streptozocin in C3H/HeN, C3H/HeJ and C57BL/6 mouse backgrounds. Intraperitoneal injections of streptozocin were used to initiate diabetes in healthy mouse backgrounds as defined by consecutive blood glucose levels >250 mg/dl. UTIs caused by uropathogenic Escherichia coli (UTI89), Klebsiella pneumoniae (TOP52), and Enterococcus faecalis (0852) were studied and diabetic mice were found to be considerably more susceptible to infection. All three uropathogens produced significantly higher bladder and kidney titers than buffer-treated controls. Uropathogens did not have as large an advantage in the TLR-4 defective C3H/HeJ diabetic mouse arguing that the dramatic increase in colonization seen in C3H/HeN diabetic mice may be partially due to diabetic-induced defects in innate immunity. Competition experiments demonstrated that E. coli had a significant advantage over K. pneumoniae in the bladders of healthy mice and less of an advantage in diabetic bladders. In the kidneys, K. pneumoniae outcompeted E. coli in healthy mice but in diabetic mice E. coli outcompeted K. pneumoniae and caused a severe pyelonephritis. Diabetic kidneys contained renal tubules laden with communities of E. coli UTI89 bacteria within an extracellular matrix material. Diabetic mice also had glucosuria, which may enhance bacterial replication in the urinary tract. These data support that this murine diabetic UTI model is consistent with known characteristics of human diabetic UTI and can provide a powerful tool for dissecting this infection in the multi-factorial setting of diabetes.