title: 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.
authors.affiliation: Veterans Affairs Medical Center, New York, New York 10010, USA.
authors.forename: J
authors.initials: J
authors.lastname: Pak
authors.forename: Y
authors.initials: Y
authors.lastname: Pu
authors.forename: Z T
authors.initials: ZT
authors.lastname: Zhang
authors.forename: D L
authors.initials: DL
authors.lastname: Hasty
authors.forename: X R
authors.initials: XR
authors.lastname: Wu
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D017124:Conserved Sequence; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004926:Escherichia coli / Q000378:metabolism*; D010861:Fimbriae, Bacterial / Q000378:metabolism*; D006026:Glycoside Hydrolases / Q000494:pharmacology; D006031:Glycosylation; D006801:Humans; D007700:Kinetics; D008358:Mannose / Q000737:chemistry / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009088:Mucoproteins / Q000737:chemistry / Q000378:metabolism* / Q000652:urine; D010641:Phenotype; D011485:Protein Binding / Q000187:drug effects; D012835:Silver Nitrate / Q000378:metabolism; D013045:Species Specificity; D059470:Tetraspanins; D014552:Urinary Tract Infections / Q000382:microbiology; D058949:Uromodulin; D060167:Uroplakin Ia; D060169:Uroplakin Ib
chemical_list: D008562:Membrane Glycoproteins; D009088:Mucoproteins; D059470:Tetraspanins; C548612:UMOD protein, human; C086451:UPK1A protein, human; C086452:UPK1B protein, human; C548613:Umod protein, mouse; C490123:Upk1a protein, mouse; C490124:Upk1b protein, mouse; D058949:Uromodulin; D060167:Uroplakin Ia; D060169:Uroplakin Ib; D012835:Silver Nitrate; D006026:Glycoside Hydrolases; D008358:Mannose