The role of cytotoxic necrotizing factor-1 in colonization and tissue injury in a murine model of urinary tract infection

Abstract

Cytotoxic necrotizing factor-1 (CNF1) is commonly found in Escherichia coli isolates from patients with urinary tract infection (UTI). To determine whether CNF1 is an important UTI virulence factor we compared the ability of a clinical E. coli UTI isolate and a CNF1-negative mutant of that isolate to colonize and induce histological changes in the urinary tract in a murine model of ascending UTI. We found no evidence that the mutant strain was attenuated.

Mutation of the Gene Encoding Cytotoxic Necrotizing Factor Type 1 (cnf1) Attenuates the Virulence of UropathogenicEscherichia coli

“…That the conclusions of this study and the report of Johnson et al (13,26) are contradictory may be explained, in part, on the basis of differences in certain experimental variables used by the two groups. The parameters that are known to alter the severity and time course of single-strain challenge studies in the mouse UTI model include the following.…”

“…Prior to this report, the evidence in favor of such a proposal was primarily based on epidemiological findings (3,6,35,45) and, more indirectly, the cytopathic effects of CNF1 on a human bladder epithelial cell line, 5637 (34). The evidence against such a theory was recently presented by Johnson and colleagues (26). Those investigators used the same general approach that we employed in our investigation: a comparison of the net growth and histological damage induced by a CNF1-positive UPEC strain to those of its isogenic cnf 1 mutant in a mouse model of ascending UTI.…”

“…In contrast, the data could also indicate that CNF1 does not play a role in the infection of BALB/c mice. Since Johnson et al used CBA/J/Hsd mice (26), perhaps the absence of a demonstrable effect of CNF1 on the urovirulence of F11 could reflect their choice of mouse strains for these experiments. Third, the time in infection at which the comparison between a CNF1-positive and a CNF1-negative strain was made had an impact in our studies of mice that were inoculated with single bacterial strains (earlier was generally better at a comparable dose).…”

“…Indeed, Johnson and colleagues previously reported that cystitis isolates colonize the mouse bladder and urine better than do pyelonephritis isolates whereas pyelonephritis isolates colonize the kidneys at higher levels. The strain used by Johnson et al for their analysis of the contribution of CNF1 to the urovirulence of E. coli in the mouse model was F11, an isolate from the urine of a patient with symptoms of cystitis (26). In our experiments, we primarily examined CP9, a strain isolated from the blood of a patient (41).…”

Cytotoxic Necrotizing Factor 1 and Hemolysin from Uropathogenic Escherichia coli Elicit Different Host Responses in the Murine Bladder

“…In a mouse model of ascending UTI, our laboratory previously showed that a UPEC isolate that expresses CNF1 elicits significantly more interstitial and submucosal edema and neutrophil infiltration in the bladder than an isogenic cnf1-negative strain, despite the fact that both strains colonize the urinary tract equivalently (13)(14)(15)(16). Conversely, previous work from Johnson et al suggested that CNF1 does not contribute to UPEC colonization of or pathological alterations in the bladder (17). However, the inocula used in their study were nearly 100-fold higher than those used in our study, so the effects of CNF1 could have been masked by those of lipopolysaccharide (LPS) and other UPEC virulence factors.…”