Tamm-Horsfall Protein Binds to Type 1 Fimbriated Escherichia coli and Prevents E. coli from Binding to Uroplakin Ia and Ib Receptors

Abstract

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 adhesins 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 fimbriated E. coli, the main cause of UTI. The binding was highly specific and saturable and could be inhibited by D-mannose and abolished by endoglycosidase H treatment of THP, suggesting that the binding is mediated by the high-mannose moieties of THP. It is species-conserved, occurring in both human 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 adhesin characteristic of those prevalent in UTI isolates compared with the one prevalent in isolates from the large intestine of healthy individuals. Finally, a physiological concentration of THP completely abolished the binding of type 1 fimbriated E. coli to uroplakins Ia and Ib, two putative urothelial receptors for type 1 fimbriae. These results establish, on a functional level, that THP contains conserved high-mannose moieties capable of specific interaction with type 1 fimbriae and strongly suggest that this major urinary glycoprotein is a key urinary anti-adherence factor serving to prevent type 1 fimbriated E. coli from binding to the urothelial receptors.The adhesion of Escherichia coli, the most common cause of urinary tract infection (UTI), 1 to urothelial cells is a crucially important first step in UTI pathogenesis (1-5). This adhesion process frequently requires filamentous surface appendages of uropathogenic E. coli that are called fimbriae, or pili. Epidemiological studies have shown that Ͼ90% of all E. coli isolates from UTI patients elaborate type 1 fimbriae (also named mannose-sensitive fimbriae) (4, 6, 7). Although controversies existed for several years, recent investigations have unequivocally documented the importance of type 1 fimbriae as a major urovirulence factor. For instance, of the nine most common E. coli virulence factors, the genes for type 1 fimbriae emerged as the only trait common in all 203 UTI isolates examined (8). In addition, 26% of the 203 strains were positive only for type 1 fimbrial genes and were negative for the eight other urovirulence factors tested, including P, S, and Dr fimbriae. In experimental mouse models, type 1 fimbriae were shown to be indispensable for bladder colonization and infection (9). Conversely, systemic immunization of mice with the FimH tip adhesin of type 1 fimbriae reduced bladder colonization of E. coli by 99% even in neutropenic mice, suggesting that blocking type 1 fimbriae could completely abolish E. coli adhesion (10). Further evidence supporting an important role of type 1 fimbriae ...

In vivo Evaluation of FimH Antagonists – A Novel Class of Antimicrobials for the Treatment of Urinary Tract Infection

“…It is able to neutralize UPEC by binding to their type 1 pili and it thereby prevents the adhesion to urothelial cells. [23] Interestingly, it is highly conserved during evolution and THP-deficient mice are more susceptible to UTI. [24] Once the bacteria are trapped by THP, the THP/bacteria cluster is eliminated by the urine flow from the urinary tract.…”

CEACAM6 acts as a receptor for adherent-invasive E. coli, supporting ileal mucosa colonization in Crohn disease

“…Several glycosylated receptors for type 1 pili have been documented, such as glycosylphosphatidylinositol-anchored (GPI-anchored) protein CD48, Tamm-Horsfall protein (THP), and various family members of carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) (16)(17)(18)(19)(20). Western blot analysis of total protein extract from ileal specimens of 9 CD patients, taken in both involved and uninvolved areas, and of 9 controls showed a strong expression of CEACAM5 (also called CEA or CD66e) and CEACAM6 (also called CD66c or non-crossreacting antigen [NCA]) in the ileal mucosa of CD patients in both involved and uninvolved areas ( Figure 3A).…”

Urinary Tract Immunology

“…Thus, more active mechanisms, like umbrella cell exfoliation (6) that occurs by an apoptosis-like mechanism and is promoted by FimH (7) remove adherent UPEC. TammHorsfall protein (THP) is a high-molecular-weight protein present in human urine (8) that binds E. coli fimbriae (9) by virtue of its mannose moieties, inhibiting fimbrial interaction with uroplakin receptors (10). This phenotype translated in vivo as thp−/− mice were unable to control lower-UTI (11).…”