Tamm-Horsfall protein binds to type 1 fimbriated Escherichia coli and prevents E. coli from binding to uroplakin Ia and Ib receptors

The adherence of uropathogenic Escherichia coli to the urothelial surface, a critical first step in the pathogenesis of urinary tract infection (UTI), is controlled by three key elements: E, coli adhesins, host receptors, and host defense mechanisms. Although much has been learned about E. coli adhe sins and their urothelial receptors, little is known about the role of host defense in the adherence process, Here we show that Tamm-Horsfall protein (THP) is the principal urinary protein that binds specifically to type 1 fi mbriated E. coli, the main cause of UTI, The binding was highly specific an d saturable and could be inhibited by D-mannose and abolished by endoglycos idase H treatment of THP, suggesting that the binding is mediated by the hi gh-mannose moieties of THP, It is species-conserved, occurring in both huma n and mouse THPs. In addition, the binding to THP was much greater with an E, coli strain bearing a phenotypic variant of the type 1 fimbrial FimH adh esin characteristic of those prevalent in UTI isolates compared with the on e prevalent in isolates from the large intestine of healthy individuals, Fi nally, a physiological concentration of THP completely abolished the bindin g of type 1 fimbriated E. coli to uroplakins Ia and Ib, two putative urothe lial receptors for type 1 fimbriae, These results establish, on a functiona l level, that THP contains conserved high-mannose moieties capable of speci fic interaction with type 1 fimbriae and strongly suggest that this major u rinary glycoprotein is a key urinary anti-adherence factor serving to preve nt type 1 fimbriated E, coli from binding to the urothelial receptors.