Escherichia coli that express Dr fimbriae and related adhesins recognize the common receptor decay accelerating factor. E. coli strains that express adhesins of the Dr family were postulated to be associated with cystitis (30-50%), pregnancy-associated pyelonephritis (30%), and chronic diarrhea (50%). In this study, we investigated the hypothesis that E. coli

Escherichia coli Dr adhesin and decay-accelerating factor (DAF) receptor-mediated interaction was proposed as the mechanism of ascending urinary tract infection (UTI) and chronic interstitial nephritis. This report provides novel evidence for Dr fimbriae operon-mediated invasive capacity of Dr+ E. coli. Insertional mutants draE, draC, and draB, and adherent draD and UV-inactivated BN406 were unable to enter HeLa cells. Complementation of the dra mutation restored invasiveness. Internalization was inhibited by anti-Dr fimbriae IgG (100%), anti-SCR-3 domain of DAF (75%), and nocodazole (95%). Increased receptor-ligand density occurred at the site of internalization. Internalized Dr+ E. coli did not significantly multiply in the HeLa cell line. Accordingly, the dra operon and DAF were required for microtubule-dependent internalization of E. coli to HeLa cells. The relatively low invasion and multiplication rates of Dr+ E. coli may hypothetically contribute to the postattachment steps of ascending UTI and chronic renal infection.

Dr-fimbriatedUrinary tract infections (UTI) are among the most common bacterial infections in humans, and Escherichia coli is the predominant etiologic agent (14). About 10 to 20% of women and 12% of men experience symptomatic UTI at some point in their lives (14,19). The characteristic feature of UTI is its marked tendency to recur. About 25% of women with a first episode of UTI have a second episode within 6 months (8). An ascending route of infection is the most common pathogenic mechanism and involves the spontaneous ascent of bacteria from the urethra to the bladder and to the kidneys. Adhesions of uropathogenic E. coli are specific lectin-like structures which are expressed by the bacteria and enable them to attach to and colonize the uroepithelium and to initiate infectious processes (14). Epidemiological studies of clinical isolates from UTI and diarrhea suggest that children and pregnant women are predisposed to infection by the E. coli-expressing Dr family of adhesins. As many as 50% of isolates from children with protracted diarrhea and 25 to 50% of isolates from children with cystitis express Dr adhesins (1, 10, 25), in contrast to 10 to 15% of isolates from adults, especially young healthy women, with cystitis (37, 39). E. coli Dr adhesins are associated with 30% of cases of pyelonephritis in pregnant women, particularly during the third trimester of gestation (26). The expression of Dr adhesins has been associated with a twofold-increased risk of a second episode of UTI (9). The members of the Dr family of adhesins, including Dr, Dr-II, AFA I, AFA III, and F1845, have a similar genetic organization and recognize decay-accelerating factor (DAF or CD55) as their cellular receptor (27,31).DAF is a complement-regulatory protein which protects host tissues from damage by the autologous complement system by inhibiting the formation and accelerating the decay of C3 and C5 convertases (24). DAF has a wide tissue distribution; for example, it is present on epithelial surfaces of the gastrointestinal mucosa, exocrine glands, renal pelvis, ureter, bladder, cervix, and uterine mucosa (22). Using an indirectimmunofluorescence technique, we also demonstrated that the purified Dr fimbria binds to these sites, including the renal epithelium in the urinary tract (28). DAF is a 70-kDa glycoprotein and consists of five domains, i.e., four short consensus repeats (SCR1 to SCR4) followed by a serine-threonine-rich (ST-rich) domain, and is attached to the cell membrane by a glycosylphosphatidylinositol (GPI) anchor (24). The other membrane-bound complement receptors of the regulators of complement activation family are membrane cofactor protein (MCP or CD46), and complement receptors 1 and 2 (CR1 or CD35, CR2 or CD21). Recent reports suggest that these complement receptors are targeted as cellular receptors by several bacteria, viruses, and parasites (2,23,33). E. coli expressing the Dr family of adhesins was the first described example of a pathogen that targets DAF as its cellular receptor (29). Of particular interest...

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The pathogenic mechanism of recurrent or chronic urinary tract infection is poorly understood. Escherichia coli cells bearing Dr fimbriae display unique tropism to the basement membrane (BM)-renal interstitium that enables the bacteria to cause chronic pyelonephritis in experimental mice. The renal receptors for Drfimbriated E. coli are type IV collagen and decay-accelerating factor (DAF). We hypothesized that type IV collagen receptor-mediated BM-interstitial tropism is essential for E. coli to cause chronic pyelonephritis. To test the role of the type IV collagen tropism of Dr-fimbriated E. coli in renal persistence, we constructed an isogenic mutant in the DraE adhesin subunit that was unable to bind type IV collagen but retained binding to DAF and examined its virulence in the mouse model. The collagen-binding mutant DrI113T was eliminated from the mouse renal tissues in 6 to 8 weeks, while the parent strain caused persistent renal infection that lasted at least 14 weeks (P < 0.02). Transcomplementation with the intact Dr operon restored collagen-binding activity, BM-interstitial tropism, and the ability to cause persistent renal infection. We conclude that type IV collagen binding mediated by DraE adhesin is a critical step for the development of persistent renal infection in a murine model of E. coli pyelonephritis.