真菌感染过程中的免疫调节分子机制研究

Fungal infection is a main cause leading to the high lethal rate in immune-compromised or immune-deficient patients. The components of the fungal cell wall can bind to the Pattern Recognition Receptor (PRR) on the host innate immune cells to induce innate immune responses. Elucidating the mechanism by which PRR recognizes fungal cell wall components and the downstream signaling events has been the main area for investigating the immunogenicity of fungi. Our recent studies have shown that Dectin-2 and Dectin-3, two C-type lectin receptors (CLRs), form heterodimers to recognize α-mannan and activate the CARD9-dependent NF-κB signaling pathway. The combination of heterodimers or homodimers can significantly increase the diversity and specificity that host immune system senses fungal infection. We have also found that CARD9, a key molecule for mediating CLR-induced NF-κB activation, can induce ERK activation and downstream inflammatory cytokine secretion through Syk phosphorylation-induced Ras-GRF1 and H-Ras activation. .The proposed study will focus on characterizing the components of fungal cell wall for their elicited signal transduction in innate immune cells. Our goals are (1) to determine the diversity and specificity of PRRs that impact their recognition of α-mannan and β-glucan, and to identify the receptor for Chitin, one of main components in fungal cell wall, and characterize its downstream signaling events; (2) to determine how CARD9 regulate the crosstalk between NF-κB and ERK signal pathway to induce anti-fungal immunity; (3) to generate CARD9 knock-in mouse model containing mutations found in human patients, and determine how CARD9 mutations impact fungal infection in human patients. These studies will determine the molecular interaction between the fungal immunogen and PRR from the host immune system, and provide potential targets for designing therapeutic agents against fungal infection.

真菌感染是造成临床免疫功能低下或缺陷病人死亡的重要原因，真菌表面成份可结合宿主细胞的模式识别受体(PRR)诱发机体免疫反应。申请人最新研究发现，Dectin-3和Dectin-2形成异源二聚体识别α-mannan激活NF-κB通路，这种同源或异源二聚体的组合模式提高了机体识别真菌的多样性和特异性；CARD9作为真菌感染激活免疫反应的关键分子，除介导NF-κB活化外，还通过H-Ras激活ERK通路抵御真菌感染。.本项目从真菌表面成份入手，探讨α-mannan和β-glucan激活受体的多样性及特异性，发现鉴定新型的C型凝集素受体；阐明CARD9在激活NF-κB等通路抵御真菌感染的作用；在临床病人发现的CARD9突变基础上，构建小鼠模型研究该突变致病的分子机制。这些问题的解决，有助于阐明真菌表面成份通过PRR与机体免疫系统相互作用的分子机制，为日益严重的真菌感染疾病提供新的分子靶标和治疗策略。

真菌感染是造成临床免疫功能低下或缺陷病人死亡的重要原因，真菌表面成份可结合宿主细胞的模式识别受体(PRR)诱发机体免疫反应。申请人最新研究发现，Dectin-3和Dectin-2形成异源二聚体识别α-mannan激活NF-κB通路，这种同源或异源二聚体的组合模式提高了机体识别真菌的多样性和特异性；CARD9作为真菌感染激活免疫反应的关键分子，除介导NF-κB活化外，还通过H-Ras激活ERK通路抵御真菌感染。.本项目从新的宿主C型凝集素受体CD23的鉴定及抗真菌感染功能研究、CARD9、JNK1等关键分子在抗真菌感染免疫应答中的分子机制研究、药物靶点可行性研究、CARD9分子在炎性肠病和肠癌发生过程中的作用研究、CARD9临床突变在ABPA、IBD疾病中的分子机制研究、临床相关性研究等，系统阐明了从CLR到下游CARD9、JNK1等分子在抗真菌感染免疫应答中的作用和分子机制，揭示了CARD9临床突变的发病机制，为临床预防、诊治真菌感染提供了新的策略和药物靶点。除此之外，我们还对NF-κB信号通路相关分子的功能进行了研究，也取得了重要的发现。