Increased Susceptibility of Secretor Factor Gene Fut2 -Null Mice to Experimental Vaginal Candidiasis

Abstract

Fut2-LacZ-null mice, which are a model of the human ABO and Lewis nonsecretor group, display increased susceptibility to experimental yeast vaginitis, indicating a role for ␣(1,2)fucosylated cervical glycans in mucosal defense. However, the lack of significant effect of competitive inhibition by exogenous neoglycoproteins in this study emphasizes the complexity of Candida-epithelial cell adhesion events.Recurrent vulvovaginal candidiasis (RVVC) is a mucosal infection caused by the opportunistic fungus Candida albicans which affects up to 5 to 10% of women of reproductive age (22,23). The immune response elicited during an episode of RVVC differs from the classical host defense mechanism, as infection occurs despite normal Candida-specific Th1-type cellmediated immunity (9, 16). Protection from RVVC is believed to be acquired locally, possibly involving incompletely defined vaginal epithelial carbohydrate adhesion molecules (2, 24).A common null mutation within the coding region of the ␣(1,2)fucosyltransferase gene, FUT2 (secretor factor gene), leads to ABO and Lewis histo-blood group antigen nonsecretion from mucosal tissues in approximately 20% of humans, with ethnic variation (13,14). Nonsecretor status has been associated with differences in susceptibility to several infections, including infections with Norwalk virus (15), human immunodeficiency virus (1), Escherichia coli (17, 21), Staphylococcus aureus (20), Campylobacter jejuni (19), calicivirus (18), and C. albicans (5). While the mechanism of how C. albicans interacts with nonsecretors is not known, a host-microbe adhesion mechanism is supported by in vitro studies that have demonstrated binding of various fucosylated oligosaccharides to germ tubes of C. albicans (3,4,6,25). We report here the development of a mouse model for the nonsecretor phenotype to test the importance of ␣(1,2)fucosylated glycans in vivo during experimental vaginal candidiasis.Absence of endocervical and vaginal ␣(1,2)fucosylated glycans in Fut2-LacZ-null mice. The expression pattern of Fut2 and resulting ␣(1,2)fucosylated glycans in the female lower reproductive tract was examined in 8-to 10-week-old female mutant mice (Fut2-LacZ-null mice) that contained a targeted replacement of the Fut2 open reading frame with a bacterial lacZ reporter gene (8). The original mutant mice were backcrossed 10 generations to C57BL/6J mice (Jackson Laboratory, Bar Harbor, Maine), and the resulting congenic strain used for this study was designated B6.129X1-Fut2 tm1Sdo (MGI accession ID no. 2183220). A second line of mutant mice lacking the coding region of another ␣(1,2)fucosyltransferase gene, Fut1, was similarly backcrossed for 10 generations to C57BL/6J mice and was designated B6.129X1-Fut1 tm1Sdo (MGI accession ID no. 2183219) and used as genetic background controls.Using a 5-bromo-4-chloro-3-indolyl␤-D-glucuronic acid (XGal) staining method (7), specific nuclear LacZ staining was detected in the glandular and lumenal epithelium of the endocervix of Fut2-LacZ-null mice in estrus (Fig. 1A), but ...

Widespread balancing selection and pathogen-driven selection at blood group antigen genes

“…In particular, the association between infections and BGA polymorphisms has been extensively investigated, although conclusive results have been obtained in a minority of cases. For example, specific BGA alleles have been shown to alter susceptibility to malaria (Moulds and Moulds 2000), while FUT2 variants (Lewis system) influence the predisposition to Norwalk virus (Lindesmith et al 2003) and Campylobacter (Ruiz-Palacios et al 2003) infection, as well as to vulvovaginal candidisis (Hurd and Domino 2004) and urinary tract infections (Schaeffer et al 2001).…”

Cervical mucins carry α(1,2)fucosylated glycans that partly protect from experimental vaginal candidiasis

“…In our animal model of nonsecretors, Fut2-null mice, we reported an increased susceptibility to experimental vaginitis 16. Fut2 is expressed in secretory cells of uterine and endocervical glandular epithelium, but expression was not detected at the major site of Candidal adhesion and invasion, i.e.…”

The role of oligosaccharides from human milk and other sources in prevention of pathogen adhesion

“…The authors suggest that the H disaccharide-containing cell surface glycoconjugates may act as host receptors for Candida albicans on the buccal mucosa as a part of a complex adhesion mechanism probably requiring multireceptor specificities given that total adhesion inhibitions were never obtained throughout the study. Other studies have shown that ABH non-secretors have a higher incidence of candidiasis (BurfordMason, Weber & Willoughby, 1988; Hurd & Domino, 2004;Lamey et al, 1991), suggesting that fucosylated oligosaccharides may be suitable as functional food ingredients for individuals who have a high susceptability to oral candidiasis. The potential of milk oligosaccharides in preventing adherence of other fungal species remains unknown.…”