重要内质网塑形蛋白在疟原虫致病性方面的作用研究

细胞内的寄生性病原体会通过分泌来改装宿主细胞，以用于自身生长发育。引起疟疾的疟原虫在入侵红细胞后，也通过分泌大幅修饰被感染红细胞的表面，从而实现营养摄取和免疫逃逸。因此，干扰疟原虫的蛋白质分泌是防治疟疾的有效策略之一。然而，疟原虫分泌路径极其复杂，其机制和调控方式都不清楚。前期研究显示，细胞分泌与内质网形态功能密切相关，但疟原虫的内质网也未被研究过。我们发现介导酵母管状结构发生的内质网塑形蛋白YOP1，以及内质网融合素SEY1均在疟原虫中有同源蛋白，假设这些蛋白也调控疟原虫内质网形态，就有可能直接破坏到蛋白分泌，并进而影响疟原虫的致病性。由此，我们计划分别构建YOP1和SEY1缺失的人疟及鼠疟虫株，利用蛋白组学等方法分析突变虫株的分泌缺陷，并阐明内质网形态维持在疟原虫生长发育、侵染运动、脑疟发生等过程中的作用机制。这些研究将累积内质网调控分泌的重要依据，也将提供疟疾的防治新思路和手段。

Intracellular parasitic pathogens secrete proteins to manipulate their host cells into a favorable environment for themselves. Plasmodium parasite, the causative agents of malaria, is especially adapted for this task; it drastically remodels the surface of the infected red blood cells for the purposes of nutrient absorption and immune escape. Therefore, molecular tools that disrupt protein secretion will be powerful for preventing malaria. However, the secretory pathways of Plasmodium are complicated, with not much known about the mechanisms and regulation. Previous research suggests that secretion is highly depended on the morphology and function of the ER. Unfortunately, the ER of the Plasmodium parasite is also not well studied. We found that the yeast ER tubule-forming protein YOP1 and ER fusogen SEY1 have paralogs in Plasmodium. If these proteins regulate the morphology of the parasitic ER as expected, they likely impose impact on protein secretion, which in turn influence the virulence of the parasite. To test this hypothesis, we aim to generate deletion lines of YOP1 and SEY1 in both human and rodent-infecting parasites, and analyze defects in secretion by proteomic approaches. Finally, we will investigate the roles of ER shaping in parasite development, movement and invasion, and pathogenesis of the deadly cerebral malaria. These findings will reveal mechanistic details in ER-regulated secretion, and provide new insight into malaria prevention.