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This Article Full Text Full Text (PDF) All Versions of this Article: 286/4/F795    most recent 00357.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (44) Citing Articles via Google Scholar Google Scholar Articles by Mo, L. Articles by Wu, X.-R. Search for Related Content PubMed PubMed Citation Articles by Mo, L. Articles by Wu, X.-R.

Ablation of the Tamm-Horsfall protein gene increases susceptibility of mice to bladder colonization by type 1-fimbriated Escherichia coli

Departments of ¹Urology and ³Microbiology, Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York 10016; ⁴Veterans Affairs Medical Center in New York, New York 10010; and ²Department of Anatomy and Neurobiology, University of Tennessee, Memphis 38163 and Veterans Affairs Medical Center, Memphis, Tennessee 38104

Submitted 9 October 2003 ; accepted in final form 5 December 2003

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.

innate host defense; gene knockout; urinary bladder infection; FimH adhesin

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