子孢子活化肝细胞内补体及其促进肝期疟原虫发育的机制研究

疟疾是全球重要的公共卫生问题。疟疾消除计划的提出使得疟疾预防策略的制定显得尤为迫切，而阐明肝期疟原虫发育机制是制定有效疟疾预防策略的前提。课题组前期研究发现，与现有关于补体抗病原体感染的观点相反的是，疟原虫子孢子却可利用肝细胞内补体的活化促进其在肝细胞内发育，但具体的分子机制并不清楚。鉴此，本项目拟一方面采用组学和基因修饰技术探讨不同种属疟原虫子孢子活化肝细胞内补体的分子机制，及其在促进肝期疟原虫发育中的作用；另一方面则采用C3、C3aR和C5aR等敲除小鼠，从体内外系统地探讨肝细胞内补体活化成分C3a、C5a等在促进肝期疟原虫发育中的作用及相关信号通路。该研究将不但揭示疟原虫新的免疫逃避机制，而且将有助于我们对肝期疟原虫发育机制的理解，更重要的是可为预防性疟疾药物的研制提供新思路和新靶点。

Malaria still is one of the most important global diseases. It is urgent to design prophylaxis strategy to eliminate malaria worldwide, and the designation of effective prevention measures requires us to understand the underlying mechanism of the development of EEFs in hepatocytes. Our preliminary study has shown that the local C3 in hepatocytes could greatly promote the intrahepatic parasite development, but the underlying mechanism is still unknown. In this proposal, we aim to investigate the mechanism of the invasion of sporozoites to activate the local C3 of hepatocytes, and its role in the liver-stage development; we would also aim to examine whether the C3a/C3aR and C5a/C5aR are involved in the regulation of selective autophagy of EEFs, and the development of malaria liver stage. This will reveal a novel immune evasion strategy of EEFs, and help us to understand the development of EEFs. This project would also shed us a light on prophylaxis strategy to finally eliminate malaria all over the world.