白念珠菌激活IFN-α介导的PD-L1/PD-1通路促进T细胞凋亡的分子机制研究

Under the existing antifungal treatment, the mortality rate of invasive Candida albicans infection is still as high as 40%, so the development of new antifungal drugs is imminent. A large number of C. albicans spread into the blood will cause immune disorders and serious inflammatory pathological damage. Our previous studies found that systemic C. albicans infection could cause serious thymus atrophy in a short period of time. A large number of T cells in the spleen undergone apoptosis, which in turn weakened the protective immune responses of Th1 and Th17 cells. After treatment with fluconazole and Caspase-3 inhibitors or PD-1 antibodies, the survival rate of systemic C. albicans infected mice is significantly improved, but the mechanism of T cell apoptosis induced by C. albicans is still unclear. Further studies showed that the expression of PD-L1 on the surface of innate immune cells of spleen was significantly increased after C. albicans infection. At the same time, type I interferon IFN-α, which could up-regulate PD-L1 expression, continued to rise in serum of mice infected with C. albicans. Therefore, this study will focus on the role of PD-L1/PD-1 pathway in T cell apoptosis during systemic C. albicans infection and elucidate the mechanism and antigens of C. albicans stimulating innate immune cells to produce IFN-α, which may up-regulate the PD-L1 expression. Finally, this research will reveal the way in which C. albicans suppresses immune responses and provide new ideas and strategies for antifungal immunotherapy.

在现有抗真菌药物治疗下，系统性念珠菌感染的死亡率仍高达40%，研发新的抗真菌药物迫在眉睫。大量白念珠菌播散入血后会造成机体免疫紊乱和过度炎症反应，进而造成免疫失能。申请人前期研究发现系统性白念珠菌感染短时间内会导致大量脾脏T细胞发生凋亡，削弱后期发挥保护作用的Th1和Th17免疫应答。利用抗T细胞凋亡的Caspase-3抑制剂或PD-1抗体协同氟康唑治疗后，系统性白念珠菌感染小鼠生存率明显提高，但关于白念珠菌引起T细胞凋亡的机制尚不清楚。白念珠菌感染后脾脏固有免疫细胞表面PD-L1表达显著增强，血清中上调PD-L1表达的I型干扰素IFN-α持续升高；因此，本课题将主要研究系统性白念珠菌感染过程中PD-L1/PD-1通路在T细胞凋亡中的作用，阐明IFN-α上调PD-L1表达的机制，明确白念珠菌刺激IFN-α产生的关键抗原，揭示白念珠菌抑制免疫应答的方式，为抗真菌治疗提供新思路新方法。

系统性真菌感染是人类健康的重要威胁，在现有抗真菌药物治疗下死亡率仍高达40%，寻找新的抗真菌治疗策略至关重要。抗真菌免疫治疗是近年来真菌感染研究的重要方向，在本项目的资助项，课题组通过研究系统性白念珠菌感染导致的大量T细胞凋亡的问题，提出了新的抗T细胞凋亡和抗PD-L1抗体治疗真菌感染的新策略，后续有望发展为临床可用的抗真菌治疗方法。本项目根据前期研究内容，通过考察系统性白念珠菌感染小鼠免疫细胞的数量，发现白念株菌感染可以导致小鼠胸腺和脾脏的T细胞数量减少，大量T细胞在感染早期发生凋亡。同时，本课题还发现FLO8基因缺失弱毒株可以作为减毒活疫苗，保护小鼠T细胞发育，促进胸腺T细胞向脾脏输出，并分化为Th1细胞，促进体内白念珠菌的清除。机制研究表明，T细胞的凋亡可能与固有免疫细胞表面PD-L1的表达有关，流式分析结果显示，白念珠菌感染早期，巨噬细胞、树突状细胞及中性粒细胞表面PD-L1的表达水平升高，其中中性粒细胞表面PD-L1上调最为显著。通过构建不同基因背景的白念珠菌及细胞壁表面的葡聚糖和甘露聚糖刺激中性粒细胞，结果发现白念珠菌表面的β-葡聚糖是刺激PD-L1上调的关键成分，且主要由Dectin-1受体识别。因此，本研究阐明了抗T细胞凋亡在系统性真菌感染中的重要作用，同时揭示了白念珠菌通过表面β-葡聚糖刺激中性粒细胞表面PD-L1上调的分子机制，有望为后续抗真菌药物研究提供新的方向。在本项目资助下，共发表影响因子5分以上的SCI论文2篇，其中1篇影响因子22.09，中文核心期刊论文1篇，申请发明专利1项。

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