暗色真菌感染常累及皮肤，病程迁延、顽固难治，影响患者生活质量甚至威胁生命。其感染相关宿主免疫机制具有皮肤及真菌特异性，是研究条件致病真菌感染中皮肤抗真菌免疫的良好模型。本课题组前期发现了8例皮肤暗色丝孢霉病患者存在CARD9缺陷以及下游的免疫异常，患者及小鼠的功能学研究提示IL-22在皮肤暗色真菌感染中发挥重要作用。为阐明IL-22相关宿主免疫在皮肤暗色真菌感染中的具体机制，本申请拟选取4种常见暗色真菌为代表，在患者皮损及小鼠感染模型中明确皮肤暗色真菌感染时IL-22的产生、来源及其通路，通过角质形成细胞系以及IL-22基因敲除小鼠的体内、体外实验，明确IL-22在皮肤暗色真菌感染中介导的免疫炎症效应、产生抗菌肽的机制和生物学效应、以及与其他细胞因子的协同效应。本课题的实施将为开展以IL-22、抗菌肽为突破的针对顽固性皮肤粘膜真菌感染的特异性免疫治疗提供重要的理论依据。

Dematiaceous fungal infections always start from skin. With its recalcitrant lesions and prolonged course, the infection can severely affect the patients’quality of life and even be life-threatening. Dematiaceous fungal infection is the ideal model to study cutaneous and subcutaneous host defense against opportunistic fungi, due to its skin specificity and fungal specificity. We previously reported CARD9 mutations and downstream immunodeficiencies in 8 patients of pheohyphomycosis. Functional studies showed marked decreased IL-22 levels against relevant fungi in both patients and Card9 KO mice compared with controls, highlightening the critical role of IL-22 in cutaneous dematiaceous fungal infections. However, the exact mechanism of how IL-22 related host defense takes part in the pathogenesis of cutaneous dematiaceous fungal infections and how it is produced is still unknown. This proposed study will choose four representatives of dematiaceous fungi, using patients’ tissue and murine model to study the production, source and signal transduction. Meanwhile, use keratinocytes and IL-22 KO mice, to study how IL-22 mediates cutaneous inflammation, triggers antimicrobial peptide secretion, and its synergetic effect with other cytokines. Our study may serve as a potential target for developing IL-22 and anti-microbial peptide related immunotherapies in intractable cutaneous fungal infections in the future.