Hormone-sensing pathway may explain gender biases in fungal infections

“It is widely known that women with high estrogen levels, due to pregnancy, oral contraceptives or hormone replacement therapy (HRT), are more prone to genital thrush like vulvovaginal candidiasis (VVC),” said senior author Rebecca Hall, PhD, a lecturer in microbial adaptation at the University of Kent in Canterbury, United Kingdom.

Although numerous studies have assessed how estrogen levels impact the host cells, “very few studies have looked at the direct impact of estrogen on C. albicans, which is the fungus causing the infection,” Hall told Contemporary OB/GYN®.

Dr Hall’s team investigates how C. albicans respond and adapt to environmental signals encountered within the human host. According to Hall, human hormones have been shown to directly affect the virulence of microbial pathogens.

“As a result, we became interested in the hypothesis that C. albicans adapts to estrogen to promote its virulence,” she said.

Because pregnant women and women taking high-estrogen-containing oral contraceptives are more susceptible to VVC than postmenopausal women, estrogen may play a role in promoting the virulence of C. albicans.

The investigators found that estrogen-induced innate immune evasion is mediated via inhibition of opsonophagocytosis through enhanced acquisition of the human complement regulatory protein, Factor H, on the fungal cell surface.

Moreover, estrogen-induced accumulation of Factor H is dependent on the fungal cell surface protein glycerol-3-phosphate dehydrogenase 2 (Gpd2).

“It is well established that women with elevated estrogen levels have an increased risk of experiencing genital thrush, and some species of bacteria have been shown to inhibit complement activation in a manner homologous to the mechanism described in our paper,” Hall said. “But the new finding is that in C. albicans, this inhibition of the complement system is directly modulated by the fungus adapting to estrogen.”

Unlike the induction of fungal morphogenesis, which appears to be limited to 17 beta-estradiol, all four tested forms of estrogen promoted innate immune evasion, “suggesting that C. albicans has evolved at least two signaling pathways that are responsive to estrogen,” Hall said.

Over the past several years, zebrafish larvae have become a superior model for studying pathogenicity mechanisms because they have an immune system that is structurally and functionally similar to the mammalian system. An ortholog of Factor H has also been identified and cloned, allowing the zebrafish model to be used to investigate the role of the complement system in microbial pathogenesis.

“The presence of estrogen in the zebrafish larval model of disseminated C. albicans infection confirms that estrogen promotes the virulence of C. albicans, suggesting that estrogen-dependent inactivation of the alternative complement system promotes the virulence of C. albicans in vivo,” Hall said.

In addition, such data indicates that women with elevated estrogen levels may be more prone to Candida infections.

“However, our knowledge of fungal virulence is in its infancy compared to other microbial pathogens,” Hall said. “Improving our understanding of the molecular mechanisms fungi use to evade our immune system and cause complex infections like VVC is paramount to the discovery of new treatment options.”

Hall and her colleagues plan to identify how Gpd2 is trafficked to the cell wall, and whether targeting Gpd2 can lead to novel treatment options for C. albicans infections.

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Hall reports no relevant financial disclosures.

Reference

1. Kumwenda P, Cottier F, Hendry AC, et al. Estrogen promotes innate immune evasion of Candida albicans through inactivation of the alternative complement system. Cell Rep. Published online January 4, 2022. doi:10.1016/j.celrep.2021.110183