How the Immune System Keeps Mucosal Fungi Under Control

The microbiome includes bacteria and fungi, many of which support human and animal health, but some fungi can also cause disease. For example, Candida albicans is a yeast that normally lives on the oral mucosa but can grow uncontrollably and cause oral thrush, and in severe cases can adopt a filamentous form, enter the bloodstream and lead to systemic infections that mainly affect immunocompromised individuals. 

“The mechanisms that keep the fungus under control on our mucosa and prevent an infection remain poorly understood,” says Salomé LeibundGut-Landmann from the Vetsuisse Faculty of University Zurich and senior author on a study recently published in Nature Microbiology. Her team used different Candida albicans strains and mice to clarify how homeostasis is maintained through the interplay between the fungus, the epithelial barrier, and the immune system. Their findings show that this fine-tuned interaction allows Candida albicans to persist on mucosal surfaces without necessarily causing damage. 

A key element in this balance is candidalysin, a toxin produced by Candida albicans that is known to attack host cells and damage protective surfaces. The researchers found that small amounts of candidalysin are actually necessary for the fungus to survive in the mouth, where the toxin acts like a door opener that helps Candida albicans anchor in the oral mucosa without injuring tissue. “The fine regulation of candidalysin determines whether Candida albicans exhibits beneficial or pathogenic properties,” explains LeibundGut-Landmann.

When Candida albicans behaves as a pathogen, it produces large amounts of candidalysin, provoking an immediate and strong inflammatory response from the immune system. In its beneficial form, the fungus produces only low levels of the toxin and can remain inconspicuous in the mucous membrane. “The fungus drives with the handbrake on, so to speak. It needs a little toxin, but too much is immediately punished.” This regulation helps decide whether Candida albicans stays a harmless colonizer or turns into a disease-causing agent.

In a second study, the team investigated how Candida albicans becomes pathogenic when immunity is weakened. They focused on interleukin 17, since individuals with a defect in the interleukin 17 gene develop oral thrush. The results show that interleukin 17-mediated immunity prevents excessive fungal growth, limits the production of large amounts of candidalysin and blocks the switch to the pathogenic form.

This protection involves “nutritional immunity,” in which interleukin 17 indirectly sequesters zinc away from the fungus. Zinc is essential for forming invasive hyphae and producing candidalysin, so limiting zinc availability restricts pathogenic traits. “Hence, interleukin 17 is a gatekeeper ensuring Candida albicans remains harmless. Loss of this gate triggers a cascade leading to fungal changes, tissue damage, and chronic disease,” adds LeibundGut-Landmann. These findings matter especially because therapies that block the interleukin 17 pathway to treat psoriasis and other inflammatory diseases can predispose some patients to mucocutaneous candidiasis, including thrush.