FADD/RIPK3轴通过抑制树突状细胞激活介导隐球菌肺部感染的分子机制研究

树突状细胞是新生隐球菌感染时宿主免疫反应的主要调控者，其激活程度和分化方向决定了感染的转归。我们前期研究发现，细胞程序性死亡相关FADD/RIPK3轴缺失促进新生隐球菌感染时树突状细胞激活，使CD4+T辅助细胞发生保护性Th1极化、1型细胞因子表达增加，然而FADD/RIPK3轴如何调控新生隐球菌感染时树突状细胞激活尚未明确。本课题拟在前期研究发现的基础上，通过对FADD/RIPK3及其介导的程序性死亡在新生隐球菌感染不同阶段对树突状细胞亚群比例、活化情况、极化、关键分子表达及信号转导的研究，明确FADD/RIPK3轴调控树突状细胞激活的机制；通过应用树突状细胞分离纯化、体外激活、功能性树突状细胞回输等，探究应用FADD/RIPK3缺陷的树突状细胞治疗或预防新生隐球菌感染的效果，为探索新型抗真菌治疗干预靶点提供理论与实验依据。

Dendritic cell is the prominent regulator of host's immune response against cryptococcal infection. Our previous work demonstrated that depletion of FADD/RIPK3 axis leads to activation of hosts' dendritic cells, resulting in Th1 polarization of CD4+ helper T cells population and up-regulated production of type I cytokines. However, the underlying mechanism remains to be dissected. Based on the preceding findings, this project is designed to investigate the activation, polarization and signal transduction of specific subsets of dendritic cells during pulmonary cryptococcosis, to further dissect the underlying mechanism of how FADD/RIPKS axis regulates activation of dendritic cells during pulmonary cryptococcosis. In another part of this project, we will explore the therapeutic/preventative effect of Ripk3-/-Fadd-/- dendritic cells during cryprococcal infection by a cell adoption method. Hopefully, all these findings will greatly advance our understanding of the host-pathogen interactions and provide promising new therapeutic strategies for cryptococcosis.