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The yeast fungus Candida albicans not only uses the toxin candidalysin to cause infections, but also to colonize the oral mucosa inconspicuously—but only in finely balanced amounts. Too little toxin prevents oral colonization, too much triggers the immune system and leads to an inflammatory defense reaction, as an international research team from Zurich, Jena, and Paris discovered.

were published in the journal Nature Microbiology.

Candida albicans is a yeast fungus that occurs naturally in the human microbiome and usually remains harmless. Under certain conditions, however, it can transform from its round yeast form into thread-like hyphae and cause infections that can have fatal consequences, especially in immunocompromised patients. In this hyphal form, Candida albicans produces the toxin candidalysin, a protein that directly attacks host cells.

"We knew that the fungal toxin candidalysin can cause disease. What is new is that it is also necessary for the fungus to survive in the mouth," explains Bernhard Hube, head of the Department of Microbial Pathogenicity Mechanisms at the Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI) and professor at the Chair of Microbial Pathogenicity at Friedrich Schiller University in Jena.

"The yeast fungus Candida albicans uses the toxin like a door opener to anchor itself in the mucous membrane. As long as it only produces it in small quantities, it remains under the radar of the immune system and survives in the oral cavity in the long term."

To clarify this connection, an international team worked with mouse models. Researchers led by Salomé LeibundGut-Landmann at the University of Zurich showed how the immune system reacts to different fungal strains.

The Leibniz-HKI in Jena contributed investigation into the genetic basis: the team used targeted interventions to modify genes that control hyphae formation and toxin production in the yeast fungus. Researchers at the Institut Pasteur in Paris then used bioinformatic analysis to orient the genetic information in an evolutionary context.

Two very different Candida strains were compared: The aggressive laboratory strain SC5314 forms long hyphae and produces large amounts of candidalysin.

As a result, the immune system reacts immediately with severe inflammation and eliminates the fungus after a short time. Strain 101, which occurs naturally in the mouth, behaves very differently: it produces only small amounts of the toxin and can thus remain inconspicuous in the mucous membrane without triggering a strong immune response.

"The fungus drives with the handbrake on, so to speak," says Hube. "It needs a little toxin, but too much is immediately punished."

"It is precisely these differences between the strains that show how important the fine regulation of candidalysin is for colonizing different niches in the body," adds Tim Schille, a doctoral researcher in the Jena team.

"Only if Candida albicans finds the correct amount, then the fungus can survive in the mouth long-term without being fought by the immune system."

The gene EED1 also plays a key role in this process. It regulates hyphae formation and thus indirectly influences the production of candidalysin. This allows the fungus to remain largely unnoticed in the oral mucosa. However, if this balance is upset, infections can develop.

"It is remarkable how well the fungus regulates its activity," says Schille. "This balance also explains why the toxin has been preserved evolutionarily: it enables the fungus to live permanently in the oral mucosa, but at the same time makes it dangerous as a potential pathogen."

The study shows that candidalysin may be an important factor in the colonization of certain areas of the body by Candida yeasts. So far, the results have only yielded cautious prospects for medicine.

"We cannot yet derive any therapeutic applications for oral Candida infections," says Hube.

"In the case of vaginal infections, however, we have already been able to show in earlier studies that the toxin can be neutralized. This can significantly reduce tissue damage caused by Candida albicans, which is typical of vaginal yeast infections."