暗色丝孢霉病是指一组由暗色真菌感染引起的皮肤、皮下组织及系统性感染，其病程迁延、顽固难治、少数可播散，严重影响患者生活质量甚至威胁生命。我们前期原创性地发现了疣状瓶霉致暗色丝孢霉病患者存在CARD9缺陷、Th17细胞反应下降以及天然免疫细胞对疣状瓶霉免疫应答的缺陷，由此提出CARD9异常所致宿主抗真菌免疫缺陷可能是该病的发病过程中重要的因素。为阐明CARD9相关的宿主免疫缺陷在暗色丝孢霉病发病中的确切机制，本申请拟选取疣状瓶霉和棘状外瓶霉为暗色真菌代表，通过体外实验明确暗色丝孢霉病中CARD9缺陷对巨噬细胞、DC细胞、中性粒细胞功能以及适应性免疫Th细胞分化的影响；并利用CARD9基因敲除小鼠模型，在体内验证CARD9相关的宿主免疫缺陷在暗色丝孢霉病发病过程中的作用。本课题的实施将为开展针对顽固性丝状真菌肉芽肿的特异性免疫治疗提供重要的理论依据。

Phaeohyphomycosis is a group of superficial, cutaneous, subcutaneous or systemic infections caused by diverse dematiaceous fungi. With its prolonged course, recalcitrant lesions and disseminations, this disease is intractable and may be life-threatening. These clinical features highly suggest that some underlying immunodeficiencies should be considered in its progression and prognosis. In a previous study published by the applicant's group, we reported CARD9 mutations in 4 patients of pheohyphomycosis, with marked decreased proportions and cytokines of Th17 cells and impaired immune responses against Phialophora verrucosa. However, the exact mechanism of how CARD9 takes part in the pathogenesis of pheohyphomycosisis is still unknown. This proposed study will focus on Phialophora verrucosa and Exophiala spinifera as the representatives of dematiaceous fungi, and study how CARD9 deficiencies affect antifungal functions of macrophages, DC cells and neutrophils, as well as Th cells differentiation. Furthermore, we will verify, in vivo, the role of CARD9 related immunodeficiencies in pheohyphomycosis through CARD9 knockout mice. Our study aims to demonstrate CARD9 related immunodeficiencies in the pathogenesis of pheohyphomycosis, and may serve as a potential target for developing new immunotherapies in the future.