IL-17–Mediated Immunity Controls Skin Infection and T Helper 1 Response during Experimental Microsporum canis Dermatophytosis

Abstract

Despite worldwide prevalence of superficial mycoses, the immune response in dermatophytosis has scarcely been investigated. In this study, we developed a model of superficial skin infection in C57BL/6 mice with Microsporum canis, a highly prevalent human pathogen. This model mimics mild inflammatory human dermatophytosis, characterized by neutrophil recruitment and fungal invasion limited to the epidermis and exhibits the establishment of a specific T helper type 17 immune response during infection. By using IL-17RA- or IL-17A/F-deficient mice we showed that, in the absence of a functional IL-17 pathway, M. canis extensively colonizes the epidermis and promotes an exaggerated skin inflammation and a shift to an IFN-γ-mediated (T helper type 1) response. IL-17 signaling was not involved in neutrophil influx to skin or fungal invasion to deeper tissues. Finally, this study shows that skin langerin-expressing cells contribute to the antifungal T helper type 17 response in vivo. In conclusion, these data directly show a dual function of IL-17 cytokines in dermatophytosis by controlling superficial infection and down-modulating a T helper type 1 antifungal response.

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

“…This is evidenced most strikingly by inborn errors in genes involved in IL-17 signaling or IL-17 induction that lead to increased susceptibility to chronic mucocutaneous candidiasis. The IL-17 pathway is also associated with immunity against other fungal diseases, at least in preclinical settings including dermatophytosis (Burstein et al, 2018), pulmonary infections with dimorphic fungi (W€ uthrich et al, 2011), and ocular mold infections (Taylor et al, 2014). Our findings highlight the relevance of type 17 immunity to the abundant mammalian skin commensal yeast Malassezia.…”

IL-17 Takes Center Stage in Dermatophytosis

“…This may be due to the usually mild course and low mortality associated with the disease, but the lack of suitable model systems to study the disease may also be a factor. Burstein et al (2018) present a novel experimental model of epicutaneous M. canis infection in mice. Application of the fungus to the shaved and lightly abraded back skin of wild-type C57BL/ 6 mice caused mild cutaneous lesions that resembled dermatophytosis in humans.…”

“…This novel dermatophytosis model is the first of its kind, and it sets the stage for investigating dermatophyte-host interactions and protective mechanisms against M. canis in skin in vivo. Burstein et al (2018) observed a selective induction of Microsporumspecific T helper (Th) type 17 cells after infection. They further showed that the IL-17 pathway was responsible for preventing uncontrolled fungal growth and overt inflammation in response to M. canis.…”

“…This is evidenced most strikingly by patients with inborn errors in the IL-17 pathway that lead to increased susceptibility to chronic mucocutaneous candidiasis (CMC) (Li et al, 2017). The novel link between dermatophytosis and the IL-17 pathway established by Burstein et al (2018) suggests that IL-17 deficiency might render patients more susceptible to dermatophytosis in addition to Candida. So far, primary immunodeficiency patients with congenital defects in the IL-17 pathway have not been reported to display increased prevalence of dermatophytosis (Li et al, 2017).…”

“…The results of Burstein et al (2018) regarding the role of IL-17 in epicutaneous M. canis infection parallels what is currently known about IL-17 immunity in the context of superficial infections with Candida albicans (Sparber and LeibundGut-Landmann, 2015). Langerin þ dendritic cells were found to contribute critically to the regulation of the M. canis-specific Th17 response (Burstein et al, 2018), reminiscent of what was reported for Th17 induction in response to epicutaneous infection with C. albicans (Igyarto et al, 2011). Burstein et al analyzed Th17 induction in the skindraining lymph nodes in M. canisinfected mice.…”