肠道病毒71型诱导外泌体促进血脑屏障通透性的分子机制研究

肠道病毒71型（EV71）感染通常引起婴幼儿手足口病（HFMD），也可通过血液循环穿过血脑屏障（BBB）入侵中枢神经系统（CNS）导致相关疾病，但是EV71调控BBB通透性及入侵CNS的分子机制尚未阐明。我们前期工作表明，EV71能诱导宿主外周血多种细胞因子表达，促进肠道细胞外泌体（Exosomes）产生。血脑屏障主要由脑微血管内皮细胞（BMEC）通过细胞间紧密连接和粘附连接组成。我们进一步发现，EV71通过感染肠道细胞诱导产生的特定分泌因子，显著下调BMEC细胞表面连接分子的表达水平，明显提高BMEC的细胞通透性。因此，我们提出假设：EV71感染肠道细胞促进外泌体产生，外泌体携带的细胞因子调控BMEC连接分子蛋白表达水平，改变细胞连接进而促进BBB通透性。本项目拟阐明EV71通过BBB入侵宿主大脑具体分子调控机制，为EV71相关神经性疾病的临床防治提供理论依据和潜在靶标。

Enterovirus 71 (EV71) usually causes hand-foot-mouth disease (HFMD) in infants. It has also been regarded to enter the central neural system (CNS) in a route of the blood across the blood-brain barrier (BBB), resulting in EV71-associated neural diseases. However, the detailed mechanism by which EV71 disrupts BBB permeability to invade CNS is still largely unknown. In our previous study, we have identified EV71 induces inflammatory cytokines production in the host sera, and promotes exosomes secretion in intestinal cells. Brain microvascular endothelial cells (BMEC) are the main consistent structure of BBB through the cellular tight junction (TJ) and adherens junction (AJ). Furthermore, our preliminary data demonstrate that EV71 infects intestinal cells to induce specifically secretory components to reduce TJ and AJ proteins level in BMEC cells, resulting in the increase of cell permeability. Thus, we raise the hypothesis that EV71 induces exosomes secretion in intestinal cells, and the circulating exosome-packaged cytokine(s) modulates TJ and AJ proteins level reduction, leading to increasing the permeability of BMEC cells and BBB. This project aims to clarify a new mechanism involved in the regulation of EV71-induced exosomes on BBB permeability, which may provide a theoretical basis and potential target for developing prevention and treatment in clinical EV71-associated neural diseases.