Malassezia fungi live on human skin. These organisms have been linked to some human skin diseases—including atopic dermatitis, which is a type of eczema induced by allergies—and to a deadly infection if they invade the bodies of premature infants. Discovering how the immune system senses and reacts to these fungal species could pave the way for the development of new treatments for the diseases caused by these organisms.
Now, a team of researchers, led by Takashi Saito at the RIKEN Research Center for Allergy and Immunology in Yokohama, has found that an immune cell protein called Mincle binds to and recognizes Malassezia species, and controls the body’s inflammatory reaction against these fungi.
The researchers began looking at Mincle because its gene is located on the mouse and human chromosome near other fungal receptor genes, and because the Mincle protein has some structural characteristics that are also found within these other fungal receptor proteins. Expressing Mincle protein on cells that were engineered to fluoresce green when Mincle signaling was activated, Saito and colleagues found that all nine of the Malassezia species they tested—but not 42 other fungal species—are able to activate Mincle signaling (Fig. 1).
The Mincle protein seems to recognize a carbohydrate on the fungi, because Mincle mutations that alter its carbohydrate-binding domain block Mincle signaling when the Malassezia fungi are present. “We have previously found that Mincle recognizes dead cells upon tissue damage and induces inflammatory responses, but this type of recognition was not mediated by carbohydrate binding,” says Saito. “Mincle thus alerts the body to different types of danger—danger originating from inside or outside the body—using differing mechanisms.”
Immune cells increase their expression of Mincle protein and secreted inflammatory proteins called cytokines when treated with Malassezia fungi, suggesting that Mincle is required for driving immune responses to these organisms. Indeed, immune cells lacking the Mincle gene were not able to efficiently increase inflammatory responses when exposed to the fungi. When one species of Malassezia was injected into mice, normal mice produced inflammatory cytokines, and had marked immune cell infiltration. These responses were blunted in mice lacking the Mincle gene.
These findings suggest that drugs that target Mincle signaling could treat diseases caused by Malassezia fungal infections on the skin or within the body. “In future work,” says Saito, “we plan to analyze if there is also a link between the Mincle protein and autoimmune disorders in humans.”
Reference
1. Yamasaki, S., Matsumoto, M., Takeuchi, O., Matsuzawa, T., Ishikawa, E., Sakuma, M., Tateno, H., Uno, J., Hirabayashi, J., Mikami, Y., Takeda, K., Akira, S. & Saito, T. C-type lectin Mincle is an activating receptor for pathogenic fungus, Malassezia. Proceedings of the National Academy of Sciences USA 106, 1897–1902 (2009).
