Type 17 immunity controls Malassezia skin infection

Florian Sparber, Corinne De Gregorio, Sarah Mertens, Martin Glatz, Immo Prinz, Federica Sallusto, Salomè Leibundgut-Landmann

Objective: The fungal microbiota of the mammalian skin is dominated by commensal fungi of the genus Malassezia. Accumulating evidence suggests that Malassezia is involved in the development and/or exacerbation of diverse skin disorders including pityriasis versicolor, dandruff, seborrhoeic eczema and atopic dermatitis. However, the causal relationship between Malassezia and the majority of these diseases remains unclear. A prerequisite for understanding the impact of Malassezia on skin pathologies is to increase the knowledge about the complex interplay between this fungus and the skin immune system. Here, we developed a novel model of Malassezia skin infection in mice to study the mammalian immune response to Malassezia and decipher the cellular and molecular mechanisms underlying fungal control in the skin in vivo. Methods: Experimental infection of mice was induced by epicutaneous application of Malassezia spp. onto unperturbed or tape-stripped ear skin. Fungal colonization was assessed by enumeration of colony-forming units in the infected skin tissue. The local immune response was determined by analyzing skin pathology, tissue cytokine induction and immune cell infiltration. The T cell response against Malassezia spp. was assessed by flow cytometry following antigen-specific re-stimulation of skin-draining lymph node cells. Human memory T cells were also analyzed for their Malassezia-responsiveness. Results: Topical application of several different Malassezia species onto the ear skin of wild type mice resulted in a high level of fungal colonization and a robust host response to the fungus, characterized by skin thickening and infiltration of inflammatory leukocytes. Skin inflammation was further augmented by tape-stripping of the ears prior to infection, indicating that Malassezia has the potential to promote skin inflammation under atopic skin conditions such as barrier deficiency. Infected animals showed activation of type 17 immunity, as evidenced by local IL-17 cytokine production in the infected tissue and by increased frequencies of Th17 cells in the draining lymph nodes. Consistently, we found that Malassezia-specific memory T cells in healthy human individuals that respond to several different Malassezia spp. belong predominantly to the Th17 subset. Underlining the relevance of IL-17 in maintaining fungal colonization, IL-17-deficient mice are unable to prevent Malassezia overgrowth in the ear skin. Conclusion: Together, our results demonstrate a critical and so far unrecognized role of type 17 immunity in keeping the balance between the skin commensal Malassezia and the mammalian immune system. This is reminiscent of what is known about the IL-17 pathway in the control of other fungal commensals such as Candida spp. and highlights the relevance of IL-17 in host protection at barrier tissues.

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