title: 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.
abstract: 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 CP9cnf(1) and that CNF1 decreases the antimicrobial activities of polymorphonuclear leukocytes. More recently, we created an Hly mutant, CP9Delta hlyA(1)::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 hlyA(1) or cnf(1) alone or together on the pathogenicity of CP9 in a mouse model of ascending UTI. To do this, we constructed an hlyA(1)-complemented clone of CP9Delta hlyA(1)::cat and an hlyA(1) cnf(1) 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 CP9Delta hlyA(1)::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.
authors.affiliation: Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814-4799, USA.
authors.forename: Yarery C
authors.initials: YC
authors.lastname: Smith
authors.forename: Susan B
authors.initials: SB
authors.lastname: Rasmussen
authors.forename: Kerian K
authors.initials: KK
authors.lastname: Grande
authors.forename: Richard M
authors.initials: RM
authors.lastname: Conran
authors.forename: Alison D
authors.initials: AD
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000378:metabolism*; D002460:Cell Line; D003556:Cystitis / Q000382:microbiology / Q000473:pathology*; D004848:Epithelium / Q000382:microbiology / Q000473:pathology; D004926:Escherichia coli / Q000472:pathogenicity*; D004927:Escherichia coli Infections / Q000382:microbiology / Q000473:pathology; D029968:Escherichia coli Proteins / Q000378:metabolism*; D005260:Female; D006460:Hemolysin Proteins / Q000378:metabolism*; D006470:Hemorrhage / Q000209:etiology; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D014521:Urethra / Q000382:microbiology; D001743:Urinary Bladder / Q000166:cytology / Q000382:microbiology / Q000473:pathology; D014552:Urinary Tract Infections / Q000382:microbiology / Q000473:pathology
chemical_list: D001427:Bacterial Toxins; D029968:Escherichia coli Proteins; D006460:Hemolysin Proteins; C036507:Hlya protein, E coli; C060296:cytotoxic necrotizing factor type 1