title: Ablation of the Tamm-Horsfall protein gene increases susceptibility of mice to bladder colonization by type 1-fimbriated Escherichia coli.
abstract: The adhesion of uropathogenic Escherichia coli to the urothelial surface of the bladder is a prerequisite for the establishment of bladder infections. This adhesion process relies on E. coli adhesins and their cognate urothelial receptors, and it also is influenced by an intricate array of defense mechanisms of the urinary system. In this study, we examined the in vivo role of Tamm-Horsfall protein (THP), the most abundant urinary protein, in innate urinary defense. We genetically ablated the mouse THP gene and found that THP deficiency predisposes mice to bladder infections by type 1-fimbriated E. coli. Inoculation of too few type 1-fimbriated E. coli to colonize wild-type mice caused significant bladder colonization in THP-knockout mice. In contrast, THP deficiency did not enhance the ability of P-fimbriated E. coli to colonize the bladder. Our results provide the first in vivo evidence indicating that under physiological conditions, the mannosylated THP can serve as an effective soluble "receptor," binding to the type 1-fimbriated E. coli and competitively inhibiting them from adhering to the uroplakin Ia receptors present on the urothelial surface. These results suggest that potential THP defects, either quantitative or qualitative, could predispose the urinary bladder to bacterial infections. The generation of THP-deficient mice established the role of THP as a first line of urinary defense and should help elucidate other potential functions of this major protein in urinary tract physiology and diseases.
authors.affiliation: Dept. of Urology, New York Univ. School of Medicine, 423 East 23 St., 18th Floor, Rm. 18064 South, New York, NY 10010, USA. xue-ru.wu@med.nyu.edu
authors.forename: Lan
authors.initials: L
authors.lastname: Mo
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Zhu
authors.forename: Hong-Ying
authors.initials: HY
authors.lastname: Huang
authors.forename: Ellen
authors.initials: E
authors.lastname: Shapiro
authors.forename: David L
authors.initials: DL
authors.lastname: Hasty
authors.forename: Xue-Ru
authors.initials: XR
authors.lastname: Wu
mesh_terms: D000818:Animals; D003556:Cystitis / Q000382:microbiology / Q000503:physiopathology*; D004926:Escherichia coli / Q000472:pathogenicity*; D004927:Escherichia coli Infections / Q000503:physiopathology*; D020022:Genetic Predisposition to Disease; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009088:Mucoproteins / Q000235:genetics* / Q000378:metabolism*; D001743:Urinary Bladder / Q000382:microbiology; D058949:Uromodulin; D014774:Virulence
chemical_list: D009088:Mucoproteins; C548613:Umod protein, mouse; D058949:Uromodulin