Oestrogen promotes innate immune evasion ofCandida albicansthrough inactivation of the alternative complement system

Abstract

Gender is a risk factor for several infections that, for many pathogens, has been linked to sex hormones impacting host immunity and directly affecting microbial virulence. Candida albicans is a commensal of the urogenital tract and the predominant cause of vulvovaginal candidiasis (VVC). Factors that increase circulatory oestrogen levels like pregnancy, the use of oral contraceptives, and hormone replacement therapy predispose women to VVC, but the reasons for this are largely unknown. Here, we investigate how adaptation of C. albicans to oestrogen impacts the fungal host-pathogen. Physiologically relevant concentrations of oestrogen promoted fungal virulence by enabling C. albicans to avoid the actions of the innate immune system. Oestrogen-induced innate immune evasion was mediated via inhibition of opsonophagocytosis through enhanced acquisition of Factor H on the fungal cell surface and was dependent on the C. albicans moonlighting protein Gpd2. Oestrogen dependent derepression of GPD2 was mediated via a non-canonical signalling pathway involving Ebp1 and Bcr1. Therefore, we propose that, in addition to affecting the antifungal potential of vaginal epithelial cells, elevated oestrogen levels predispose women to VVC by directly enhancing fungal pathogenicity. The discovery of this new hormone sensing pathway might pave the way in explaining gender biases associated with fungal infections and may provide an alternative approach to improving women’s health.