Synthetic Analogues of β-1,2 Oligomannosides Prevent Intestinal Colonization by the Pathogenic Yeast Candida albicans

Abstract

The pathogenic yeast Candida albicans displays at its cell surface ␤-1,2 oligomannosides (␤-1,2-Mans). In contrast to the ubiquitous ␣-Mans, ␤-1,2-Mans bind to galectin-3, a major endogenous lectin expressed on epithelial cells. The specific role of ␤-1,2-Mans in colonization of the gut by C. albicans was assessed in a mouse model. A selected virulent strain of C. albicans (expressing more ␤-1,2-Man epitopes) induced more intense and sustained colonization than an avirulent strain (expressing less ␤-1,2-Man epitopes). Synthetic (⌺) ␤-and ␣-linked tetramannosides with antigenicities that mimicked the antigenicities of C. albicans-derived oligomannosides were then constructed. Oral administration of ⌺␤-1,2-Man (30 mg/kg of body weight) prior to inoculation with the virulent strain resulted in almost complete eradication of yeasts from stool samples, whereas administration of ⌺␣-Man at the same dose did not. As most cases of human systemic candidiasis are endogenous in origin, this first demonstration that a synthetic analogue of a yeast adhesin can prevent yeast colonization in the gut opens the possibility of new prophylactic strategies.

Galectin-3 Induces Death of Candida Species Expressing Specific β-1,2-Linked Mannans

“…Although galectins were originally defined by the ability to bind to ␤-galactosides, some members of the galectin family, e.g., galectin-10 (42), can recognize mannose with high affinity. Furthermore, galectin-3 binds to ␤-1,2-oligomannosides isolated from the cell wall of C. albicans serotype A (51), and synthetic analogs of ␤-1,2-oligomannosides administered orally to mice prevented colonization of the intestine by C. albicans (56). However, the effect of galectin-3 binding to intact yeast was not explored, and no direct microbicidal activity for galectin-3 has been described.…”

Inactivation of CaMIT1 Inhibits Candida albicans Phospholipomannan β-Mannosylation, Reduces Virulence, and Alters Cell Wall Protein β-Mannosylation

“…They act as adhesins for human enterocytes (34) and can prevent colonization of the mouse gut by C. albicans (5). They also bind to macrophages (3,35), stimulating these cells to produce mediators or effectors of the immune response (4,36).…”

“…These oligomannoses are linked through ␤-1,2 bonds that confer a unique spatial conformation (1) recognized by innate and acquired immunity of the host. In contrast to the ubiquitous ␣-linked mannose residues, ␤-1,2 oligomannosides induce protective antibodies (2), do not bind to C-lectins but to galectin-3 (3), trigger macrophages to produce TNF-␣ (4), and inhibit mouse gut colonization (5). In C. albicans, homopolymers of ␤-1,2 oligomannosides have been shown to be associated by phosphodiester bridges with phosphopeptidomannan (PPM), 1 commonly termed mannan, and to correspond to the acid-labile fraction of this molecule (6).…”

Identification of a New Family of Genes Involved in β-1,2-Mannosylation of Glycans in Pichia pastoris and Candida albicans

“…PLM from C. albicans displays exclusively ␤-Mans (9) and has been shown to stimulate a variety of host signaling pathways (16,17). Finally, it has been demonstrated that oral administration of synthetic ␤-Mans inhibited C. albicans colonization of the intestinal track in newborn mice, whereas synthetic ␣-Man did not (18). This experimental evidence strongly suggests that ␤-Mans contribute in a very specific manner to the virulence of C. albicans.…”

“…The importance of mannan in virulence has been demonstrated by inactivation of genes involved in transfer of ␣-mannosyls on O-glycans (58) or the N-glycan outer chain (19). In parallel, experimental studies either in vitro (17,53) or in vivo (13,18), as well as clinical studies involving purified (14,53) or synthetic ␤-mannosides (18), or purified molecules selectively containing these residues (16,17), have shown that ␤-Mans also contribute to C. albicans virulence. Moreover, a separate study has revealed that the spatial conformation of ␤-Man (12) differs from the more ubiquitous ␣-Mans, most of which are shared with S. cerevisiae.…”