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Infection and Immunity, July 2008, p. 2978-2990, Vol. 76, No. 7
0019-9567/08/$08.00+0     doi:10.1128/IAI.00075-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Hemolysin of Uropathogenic Escherichia coli Evokes Extensive Shedding of the Uroepithelium and Hemorrhage in Bladder Tissue within the First 24 Hours after Intraurethral Inoculation of Mice

Yarery C. Smith,¹ Susan B. Rasmussen,¹ Kerian K. Grande,¹ Richard M. Conran,² and Alison D. O'Brien^1*

Department of Microbiology and Immunology,¹ Department of Pathology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814-4799²

Received 18 January 2008/ Returned for modification 24 March 2008/ Accepted 22 April 2008

Many uropathogenic Escherichia coli (UPEC) strains produce both hemolysin (Hly) and cytotoxic necrotizing factor type 1 (CNF1), and the loci for these toxins are often linked. The conclusion that Hly and CNF1 contribute to urovirulence is supported by the results of epidemiological studies associating the severity of urinary tract infections (UTIs) with toxin production by UPEC isolates. Additionally, we previously reported that mouse bladders and rat prostates infected with UPEC strain CP9 exhibit a more profound inflammatory response than the organs from animals challenged with CP9cnf₁ and that CNF1 decreases the antimicrobial activities of polymorphonuclear leukocytes. More recently, we created an Hly mutant, CP9hlyA₁::cat, and showed that it was less hemolytic and destructive for cultured bladder cells than CP9 was. Here we evaluated the relative effects of mutations in hlyA₁ or cnf₁ alone or together on the pathogenicity of CP9 in a mouse model of ascending UTI. To do this, we constructed an hlyA₁-complemented clone of CP9hlyA₁::cat and an hlyA₁ cnf₁ CP9 double mutant. We found that Hly had no influence on bacterial colonization of the bladder or kidneys in single or mixed infections with the wild type and CP9hlyA₁::cat but that it did provoke sloughing of the uroepithelium and bladder hemorrhage within the first 24 h after challenge. Finally, we confirmed that CNF1 expression induces bladder inflammation and, in particular, as shown in this study, submucosal edema. From these data, we speculate that Hly and CNF1 may be largely responsible for the signs and symptoms of cystitis in humans infected with toxigenic UPEC.

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* Corresponding author. Mailing address: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814-4799. Phone: (301) 295-3419. Fax: (301) 295-3773. E-mail: aobrien{at}usuhs.mil

Published ahead of print on 28 April 2008.

Editor: V. J. DiRita

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Infection and Immunity, July 2008, p. 2978-2990, Vol. 76, No. 7
0019-9567/08/$08.00+0     doi:10.1128/IAI.00075-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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