猪链球菌2型Suilysin溶血产物增加血脑屏障通透性的机制研究

Streptococcus suis serotype 2 (SS2) is a zoonotic bacterial pathogen that causes meningitis in pigs and humans, which poses a great threat to both swine industry and public health. Suilysin (Sly) is one of the most important virulence factors of SS2, which can disrupt the red blood cells (RBC) with the release of a large number of inflammatory factors. Currently, research aimed to clarify the involvement of Sly in the pathogenesis of SS2 meningitis are mostly focused on the interaction between Sly and blood-brain barrier (BBB). However, it is unclear whether the hemolytic products of Sly affect the function of BBB. Our preliminarily data showed that hemolytic products of Sly can aggravate the increased BBB permeability caused by Sly, suggested that hemolytic products of Sly may involve in the pathogenesis of SS2 meningitis. Thus, the proposed research will focus on Sly, RBC and BBB, aimed to confirm the effect of Sly hemolytic products on BBB permeability via in vitro co-culture BBB model; and further elucidate the mechanisms of Sly hemolytic products on increasing BBB permeability at both cellular level and piglets infection model. These studies would further our understandings on the pathogenesis of SS2 meningitis.

猪链球菌2型（SS2）是一种可诱发脑膜炎的人猪共患病原菌，严重威胁养猪业的发展和公共卫生安全。猪链球菌溶血素（Sly）是SS2最重要的毒力因子之一，裂解红细胞（RBC）后会释放大量的致炎分子。目前，Sly参与SS2诱发脑膜炎的机制研究多围绕Sly本身与血脑屏障（BBB）的相互作用展开，但Sly溶血产物是否影响BBB的功能尚不清楚。申请人前期的研究结果初步证实Sly溶血产物可以加重Sly所致的BBB通透性增加，提示Sly溶血产物可能参与了SS2脑膜炎的致病过程。为此，本项目拟围绕Sly、红细胞和BBB展开研究，通过建立体外共培养BBB模型，确证Sly溶血产物对BBB通透性的影响；并在细胞水平和仔猪感染模型上阐明Sly溶血产物增加BBB通透性的分子机制。以期为进一步阐明SS2脑膜炎的致病机制奠定基础。

猪链球菌2型（SS2）是重要的人兽共患病原菌，其可诱发人和动物脑膜炎等症状。猪链球菌溶血素Sly是SS2重要的毒力因子，但前期研究主要围绕Sly本身对BBB屏障功能的影响，而忽略了Sly溶血产物在SS2致病过程中的作用。为此，本研究通过细胞生物学、分子生物学等手段，系统阐述了Sly溶血产物在SS2增加BBB通透性诱导脑膜炎过程中的作用和机制。本研究首次发现Sly溶血产物在SS2感染和增加BBB通透性过程中的重要作用，并阐明Sly溶血产物中IL-33在SS2增加BBB通透性过程中的重要作用及分子机制，发现IL-33可通过抑制细胞间紧密连接蛋白Claudin5的表达、抑制p38 MAPK信号通路和增加基质金属蛋白酶MMP-9的表达，进而增加BBB的通透性，并在动物水平上进一步证实IL-33在SS2感染和增加BBB通透性的作用。该发现丰富了SS2脑膜炎致病机制的研究，为SS2脑膜炎的防控和治疗药物靶点的研究提供重要参考。