A murine model for catheter-associated candiduria

Abstract

Candiduria is a common finding in hospitalized patients with indwelling urine-draining devices. Animal models for candiduria are not well-developed and, despite its prevalence and associated mortality, candiduria is understudied. The presence of Candida in urine does not imply disease because it is also a commensal. Biofilm formation on catheters and the host-pathogen interaction are likely to be important factors that contribute to the pathogenesis. The objective of this study was to establish a candiduria model in mice with indwelling catheters. Our data demonstrate that biofilm formation on indwelling catheters and persistent candiduria can be established in mice. The study supports the concept that biofilm formation contributes to persistence. It also outlines differences between catheter-related candiduria in mice and humans. Specifically, mice exhibit higher levels of leukocyturia. In addition, mean daily fungal burden in urine in the murine model is 10- to 100-fold lower than that in humans. These important findings must be taken into consideration when using this model to study host-pathogen interaction in the setting of candiduria.

Fig. 1.

Murine model for catheter-associated candiduria. (a) Schematic of the secured indwelling catheter piece; (b) polyethelyne tube in the urethra; (c) open abdominal catheter with secured catheter.

Fig. 2.

Urine fungal burden in mice with and without catheter. (a) Comparison of mean daily urine fungal burden (c.f.u. ml⁻¹ in a 28 day period) of mice (n = 5 per group) with and without a catheter, infected intravesicularly with C. albicans. Error bars denote sd. *LysM^−/− mice with an indwelling catheter exhibit significantly higher fungal burdens than mice without a catheter (P<0.001; t-test). **Significant differences were also seen in C57BL/6 mice (P = 0.01). (b) Mean fungal burden [log₁₀(c.f.u.) ml⁻¹] in urine over 28 days in groups of mice (n = 5) with or without indwelling catheter after infection with C. albicans. Mice initially have a higher fungal burden in urine that falls and then rises again after 15 days in mice with a catheter. Error bars denote sd.

Fig. 3.

SEM of biofilm formation on catheters. (a) Biofilm formation (double arrow) is present on the inside of the catheter (single arrow). Bar, 100 µm. (b) Biofilm (double arrow) on the outside of the catheter (single arrow). Bar, 200 µm. (c) Biofilm consists of a mesh of hyphae (single arrow), yeast cells and matrix adherent to the catheter (double arrow). Bar, 2 µm.

Fig. 4.

Inflammatory response in mice with candiduria. (a) All three mouse strains (n = 5 mice per group) manifest more pronounced leukocyturia than humans and sham-infected mice. Significantly higher leukocyturia is observed in LysM^−/− mice with an indwelling catheter at day 7 than at days 14* and 21** (P<0.012; Mann–Whitney). (b) Microscopic urinalysis in LysM^−/− mice, which express GFP in WBCs, confirms that cells seen on the left in phase contrast are leukocytes and not dead yeast cells. Bar, 10 µm. (c) Non-inflamed bladder mucosa in a LysM^−/− mouse that did not have an indwelling catheter placed and underwent sham infection 14 days previously. Bar, 30 µm. (d) Inflammation in submucosal bladder tissue of an infected LysM^−/− mouse with indwelling catheter at 14 days after infection. Similar findings were seen in C57BL/6 mice with and without catheters. Bar, 30 µm. (e) Magnification (600×) of inflammatory cells in infected mice. Note that eosinophils, neutrophils and lymphocytes are detected.