Strain-level variation in Proteus mirabilis chondroitin sulfate degradation kinetics and regulation by urea

To establish infection, uropathogens must overcome several host defenses, including the glycosaminoglycan (GAG) layer coating the apical surface of the bladder urothelium. GAGs are thought to protect against urinary tract infections (UTIs) by acting as a barrier to uropathogen adherence. However, the ability of uropathogens to degrade and utilize GAGs, and the contribution of these activities toward UTI progression, are largely unknown. We previously discovered that Proteus mirabilis, a common cause of catheter-associated UTI (CAUTI), degrades the GAG chondroitin sulfate (CS). In this study, we sought to define the kinetics and regulation of CS degradation by diverse urinary P. mirabilis strains. We found variation in CS degradation kinetics between P. mirabilis strains and media types. CS degradation in one isolate, Pm123, was repressed by urea, and this repression was dependent on P. mirabilis urease activity. Complementation of the Pm123 endolyase into urea-insensitive HI4320 resulted in a urea-sensitive CS degradation phenotype, suggesting functional differences between the Pm123 and HI4320 endolyases. Sequence alignment and structural modeling identified two unique mutations within the Pm123 endolyase that may contribute to urea sensitivity. Finally, unlike urea-insensitive P. mirabilis strains, loss of CS lyase activity had no effect on Pm123 virulence in a mouse CAUTI model. Our results suggest that the kinetics and regulation of CS degradation differ between P. mirabilis strains, and regulation by urea in some strains may reduce the contribution of CS degradation to urovirulence during murine CAUTI.