Cytolethal Distending Toxin Enhances Escherichia coli Urinary Tract Infection

Cytolethal distending toxin (CDT) is a virulence factor produced by several gram-negative bacteria, including Escherichia coli, the most prevalent etiological agent of urinary tract infections (UTI). CDT causes DNA damage in eukaryotic cells, impairing host defenses by disrupting epithelial barriers, suppressing acquired immunity, and promoting pro-inflammatory responses. E. coli strains encoding CDT have been previously identified in samples from UTI patients, yet the specific function of CDT in the development or progression of UTI remains undefined. In this study, we used a mouse model of ascending UTI to determine the role of CDT during infection. An E. coli mutant strain lacking the cdtABC locus was generated and combined with wild-type bacteria to co-infect mice via transurethral inoculation. At 1-day post-inoculation, competitive indices demonstrated a significant disadvantage for the cdt mutant in urine, bladder, and kidneys. Single strain infections were also performed as a further assessment of CDT impact, demonstrating that the cdt mutant had reduced kidney colonization indicative of CDT contributions to ascending infection. Histopathological analysis of the urinary bladder and kidney tissues from mice infected with CDT-encoding E. coli demonstrated higher levels of inflammation and tissue damage within the kidneys at both 1 and 7 days post-inoculation and in the bladder at 7 days post-inoculation compared to mice infected with cdt mutant bacteria. Collectively, these findings identify a critical contribution of CDT to the progression of UTI.