The Skin Commensal Yeast Malassezia Triggers a Type 17 Response that Coordinates Anti-fungal Immunity and Exacerbates Skin Inflammation

Abstract

Graphical Abstract Highlights d The skin commensal yeast Malassezia drives type 17 immunity in the skin d Malassezia-specific human memory T cells display a Th17 phenotype d Mice deficient in IL-17AF or IL-23 show uncontrolled Malassezia growth on the skin d In the disrupted skin, IL-23 and IL-17AF promote Malasseziainduced inflammation SUMMARY Commensal fungi of the mammalian skin, such as those of the genus Malassezia, are associated with atopic dermatitis and other common inflammatory skin disorders. Understanding of the causative relationship between fungal commensalism and disease manifestation remains incomplete. By developing a murine epicutaneous infection model, we found Malassezia spp. selectively induce IL-17 and related cytokines.This response is key in preventing fungal overgrowth on the skin, as disruption of the IL-23-IL-17 axis compromises Malassezia-specific cutaneous immunity. Under conditions of impaired skin integrity, mimicking a hallmark of atopic dermatitis, the presence of Malassezia dramatically aggravates cutaneous inflammation, which again was IL-23 and IL-17 dependent. Consistently, we found a CCR6 + Th17 subset of memory T cells to be Malassezia specific in both healthy individuals and atopic dermatitis patients, whereby the latter showed enhanced frequency of these cells. Thus, the Malassezia-induced type 17 response is pivotal in orchestrating antifungal immunity and in actively promoting skin inflammation.

Horizontal gene transfer in the human and skin commensalMalassezia: a bacterially-derived flavohemoglobin is required for NO resistance and host interaction

“…This result is in contrast with previous findings in C. neoformans 28 , but it corroborates results obtained in A. fumigatus 30 . Further, the recently developed murine model for Malassezia skin infection 5 was utilized to test pathogenicity of the flavohemoglobin strains and the induction of host response. Corroborating ex vivo data, we found no differences both in terms of host tissue colonization and host inflammatory response for the yhb1 Δ mutant compared to the complemented strains (Fig.…”

“…Mice were maintained at the Laboratory Animal Science Center of University of Zurich, Zurich, Switzerland and used at 6-12 weeks in sex- and age-matched groups. Epicutaneous infection of the mouse ear skin was performed as described previously 5,84 .Briefly, Malassezia strains were grown for 3-4 days at 30°C, 180 rpm in liquid mDixon medium. Cells were washed in PBS and suspended in native olive oil at a density of 20 OD A600 /mL.…”

“…Although commensals, Malassezia species are also associated with a number of clinical skin disorders, including pityriasis versicolor, dandruff, and atopic dermatitis (AD) 4 . A recently-developed epicutaneous murine model revealed that the host responses to Malassezia are dominated by pro-inflammatory cytokine IL-17 and related factors that prevent fungal overgrowth and exacerbate inflammation under atopy-like conditions 5 . Furthermore, Malassezia species have also been implicated recently as causal agents of Crohn’s Disease/Inflammatory Bowel Disease in patients with CARD9 mutations, and in accelerating the progression of Pancreatic Adenocarcinoma in murine models and in humans 6,7 .…”

A novel mycovirus evokes transcriptional rewiring in the fungusMalasseziaand stimulates interferon-β production in macrophages

“…In a recent study, Sparber and colleagues described a murine epicutaneous infection model that involves application of Malassezia to the mouse dorsal ear following mild tape stripping (41). Colonization of host tissue (fungal load) is determined by plating homogenized tissue onto agar plates and counting colony forming units; an increase in ear thickness is used as a measurement for skin inflammation.…”

“…Moreover, for one of the two strain pairs tested, the virus-infected strain displayed increased colonization compared to their virus-cured counterpart by day 4 post-infection (Figure 4B). To determine if there was a difference in the immune response elicited by the virus-infected and virus-cured strains, we assessed the expression of interleukin-17 (IL-17), a key mediator of the host response against Malassezia on the skin (41). However, we could not detect any statistically significant differences in cytokine induction in response to virus-infected and virus-cured strains (Figure 4C), indicating that IL-17 expression was not regulated by the virus and not responsible for the observed differences in fungal load and skin thickness.…”