Objectives. Vaginal candidiasis is a common disorder in women of childbearing age. Since Candida albicans is a normal commensal of the vaginal mucosa, a long-standing question is how the fungus switches from being a harmless commensal to a virulent pathogen. Work with human subjects and in mouse disease models suggests that host inflammatory processes drive the onset of symptomatic infection. The expression of Candida virulence traits, especially those related to hyphal growth, can induce a powerful inflammatory response in the vaginal mucosa that includes strong neutrophil recruitment. Fungal cell wall molecules can also induce inflammation through activation of epithelial and immune receptors that trigger pro-inflammatory cytokines and chemokines, but pathogenic fungi can evade recognition by masking these molecules. Knowledge about which cell wall epitopes are available for immune recognition during human infection could implicate specific ligands and receptors in the symptoms of vaginal candidiasis. Methods. To address this important gap, we have directly probed the surface of fungi present in fresh vaginal samples obtained both from women with symptomatic Candida vaginitis and from women that are colonized but asymptomatic. Results. We find that the pro-inflammatory cell wall polysaccharide β-glucan is largely masked from immune recognition, especially on yeast. It is only exposed on a small percentage of hyphal cells that also tend to have enhanced levels of chitin. Enhanced β-glucan availability is only found in symptomatic patients with strong neutrophil infiltration, implicating neutrophils as the driver of these cell wall changes. Conclusions. This is especially interesting because neutrophils were recently shown to be necessary and sufficient to provoke enhanced β-glucan exposure in C. albicans, which is associated with elevated immune responses, both in vitro and in mice. Taken together, our data suggest that the architecture of C. albicans cell wall is finely regulated during vaginal candidiasis and therefore could be a target for innovative therapies.

4 / Epitope unmasking in vulvovaginal candidiasis is associated with hyphal growth and neutrophilic infiltration