The Globoseries Glycosphingolipid Sialosyl Galactosyl Globoside is Found in Urinary Tract Tissues and is a Preferred Binding Receptor In Vitro for Uropathogenic Escherichia Coli Expressing Pap-Encoded Adhesins

Abstract

Women with a history of recurrent Escherichia coli urinary tract infections (UTIs) are significantly more likely to be nonsecretors of blood group antigens than are women without such a history, and vaginal epithelial cells (VEC) from women who are nonsecretors show enhanced adherence of uropathogenic E. coli isolates compared with cells from secretors. We previously extracted glycosphingolipids (GSLs) from native VEC and determined that nonsecretors (but not secretors) selectively express two extended globoseries GSLs, sialosyl galactosyl globoside (SGG) and disialosyl galactosyl globoside (DSGG), which specifically bound uropathogenic E. coli R45 expressing a P adhesin. In this study, we demonstrated, by purifying the compounds from this source, that SGG and DSGG are expressed in human kidney tissue. We also demonstrated that SGG and DSGG isolated from human kidneys bind uropathogenic E. coli isolates expressing each of the three classes of pap-encoded adhesins, including cloned isolates expressing PapG from J96, PrsG from J96, and PapG from IA2, and the wild-type isolates IA2 and R45. We metabolically 35 S labeled these five E. coli isolates and measured their relative binding affinities to serial dilutions of SGG and DSGG as well as to globotriaosylceramide (Gb 3 ) and globotetraosylceramide (Gb 4 ), two other globoseries GSLs present in urogenital tissues. Each of the five E. coli isolates bound to SGG with the highest apparent avidity compared with their binding to DSGG, Gb 3 , and Gb 4 , and each isolate had a unique pattern of GSL binding affinity. These studies further suggest that SGG likely plays an important role in the pathogenesis of UTI and that its presence may account for the increased binding of E. coli to uroepithelial cells from nonsecretors and for the increased susceptibility of nonsecretors to recurrent UTI.Several epidemiological studies have shown that women who are nonsecretors of blood group antigens have a three-to fourfold-increased risk of developing recurrent urinary tract infection (UTI) (5,17,32). In addition, uroepithelial cells from nonsecretors have a two-to threefold-greater capacity for adherence of uropathogenic Escherichia coli than do cells from secretors (22). Colonization of the vaginal and periurethral epithelium precedes the development of E. coli UTI, and E. coli isolates expressing pap-encoded adhesins are overrepresented among isolates causing these infections (6). Uropathogenic E. coli isolates expressing pap-encoded adhesins bind to globoseries glycosphingolipids (GSLs) (6, 19), which are amphipathic molecules embedded in the outer leaflets of eukaryotic cell membranes. There are several families of GSLs which are differentiated by their molecular structures, and these molecules serve as bacterial and viral adhesion sites on mammalian cells and as markers of eukaryotic cell differentiation and oncogenesis (4).In previous investigations, we collected vaginal epithelial cells from secretors and nonsecretors and extracted the GSLs from pooled cells from women in eac...

Evidence of Commonality between Canine and Human Extraintestinal PathogenicEscherichia coliStrains That ExpresspapGAllele III

“…It has been reported that canine ExPEC strains typically do not express P fimbriae and thus are fundamentally different from human ExPEC strains (74), that they express P fimbriae and hence are similar to human ExPEC strains (71), and that they express variant forms of P fimbriae that are dissimilar to the P fimbriae of most human ExPEC strains (5,7,36,37,41,56,57), but may be present in some human isolates (36,37,41,56,57). These investigations were done before assays for the three papG alleles were generally available (12,16), before the epidemiological association of papG allele III with human cystitis had been demonstrated (12,23,59), and before it was known that receptors for PapG variant III are not confined to nonhuman hosts (5,7,46,62,63) or to humans of the A blood phenotype (36,37,56) but are present generally in humans, including within the human urogenital tract (e.g., as sialosylgalactosyl-globoside) (31,32,60,64). These more recent developments, together with the results of the present study, clarify several points.…”

“…These more recent developments, together with the results of the present study, clarify several points. They provide an explanation for the characteristic NS phenotype of pap-positive canine ExPEC strains (41), which is probably due to desialation by neuraminidase of sialosyl-galactosyl-globoside, the major receptor on human erythrocytes for the variant III PapG adhesin (32,56,60,64). They account for the seemingly discrepant MRHA results reported for canine ExPEC strains by various investigators (5,7,56,57,62,71,74), since the observed phenotypic variability is consistent with conflicting published data regarding PapG variant III (15,28,32,36,62).…”

“…(This syndrome received comparatively little attention during the first decade following the discovery of P fimbriae in E. coli strains from patients with pyelonephritis, in which context papG allele II usually predominates [12,51,59].) Second, PapG variant III is now known to bind preferentially not only to (canine-associated) Forssman glycolipid but also to several extended digalactoside-containing glycolipids which are present in the urinary tract of some humans (e.g., globo-A) (36,37,56,57) or of nearly the entire human population (e.g., sialosyl-galactosylgloboside) (32,60,64).…”

Evolution of the Chaperone/Usher Assembly Pathway: Fimbrial Classification Goes Greek

“…The pap operon encodes pyelonephritis-associated (P) fimbriae that allow uropathogenic E. coli to bind Gal␣(1-4)Gal moieties present in glycolipids expressed by kidney epithelial cells (34,310,312,318,320,321). P fimbriae are composed of a rigid helical fimbrial shaft that ends in a flexible tip fibrillum (46, 185).…”

An In Vitro Model of Fabry Disease

“…Globo-series GSL are also important host factors in the pathophysiology of several infectious diseases (36). The colonization of epithelial cells by Streptococcus suis, Escherichia coli, and Pseudomonas aeruginosa is through the recognition of globo-series GSL (37)(38)(39). Gb4 serves as the receptor for parvovirus B19, and Gb3 is required for the CD4/CXCR4-dependent fusion of HIV (40,41).…”