肺上皮细胞miR-342-3p靶向dectin-1调控烟曲霉诱导细胞天然免疫应答的机制研究

Aspergillus fumigatus is a kind of clinically important pathogenic fungus which could cause allergies, chronic aspergilloma and high mortality invasive aspergillosis. Dectin-1 receptor specifically recognizes β-1,3-glucan of Aspergillus fumigatus, mediating phagocytosis, inflammatory factors release and other innate immune responses. MicroRNAs regulate gene expression at post-transcriptional level, have close relationship to human innate immune response, but the mechanism of its regulation of dectin-1 is not clear. Our preliminary data manifest the expression level of dectin-1 receptor in pulmonary epithelial cells and dectin-1 receptor could mediate invasion of Aspergillus fumigatus inducing inflammatory cytokine release meanwhile; also the expression of miR-342-3p significantly increase during Aspergillus conidia invading pulmonary epithelial cells or using β-1,3-glucan as a stimulant, and miR-342-3p has the only conserved target site in dectin-1 3 ' UTR. This project aims to analyze the distribution and expression variation of miR-342-3p in Aspergillus fumigatus infection，and its target relationship with dectin-1in order to illuminate the regulation effect of dectin-1 downstream signaling pathways and the innate immune response of pulmonary epithelial cells induced by Aspergillus fumigatus. This thorough understanding of the molecular mechanisms of host innate immune responses could inspire us looking for possible antifungal drug targets.

临床重要病原真菌烟曲霉可引起过敏、慢性曲霉肿或病死率很高的侵袭性曲霉病。Dectin-1受体可特异性识别烟曲霉β-1,3-葡聚糖介导细胞吞噬和炎症因子释放等天然免疫应答。MicroRNA是在转录后水平调控基因表达的重要分子，与人体天然免疫应答密切相关，但对dectin-1功能的调控机制尚不清楚。我们报道了dectin-1受体在肺上皮细胞中表达并介导烟曲霉内化侵入和诱发炎症因子释放；并预测一种miR-342-3p特异性靶向dectin-1同时发现该microRNA在烟曲霉感染或β-1,3-葡聚糖刺激肺上皮细胞时表达升高。据此，本项目拟深入分析miR-342-3p在烟曲霉感染过程中的分布与表达变化，解析其与dectin-1之间的靶向关系，及对dectin-1下游信号通路和烟曲霉诱导肺上皮细胞天然免疫应答的调控机制。这对透彻理解宿主天然免疫应答的调控机制，寻找可能抗真菌感染药物靶点具有重要意义。