PDF(Pubmed)
Abstract：
The human blood-brain barrier (BBB) comprises a single layer of brain microvascular endothelial cells (HBMECs) protecting the brain from bloodborne pathogens. Meningitis is among the most serious diseases, but the mechanisms by which major meningitis-causing bacterial pathogens cross the BBB to reach the brain remain poorly understood. We found that Streptococcus pneumoniae, group B Streptococcus, and neonatal meningitis Escherichia coli commonly exploit a unique vesicle fusion mechanism to hitchhike on transferrin receptor (TfR) transcytosis to cross the BBB and illustrated the details of this process in human BBB model in vitro and mouse model. Toll-like receptor signals emanating from bacteria-containing vesicles (BCVs) trigger K33-linked polyubiquitination at Lys168 and Lys181 of the innate immune regulator TRAF3 and then activate the formation of a protein complex containing the guanine nucleotide exchange factor RCC2, the small GTPase RalA and exocyst subcomplex I (SC I) on BCVs. The distinct function of SEC6 in SC I, interacting directly with RalA on BCVs and the SNARE protein SNAP23 on TfR vesicles, tethers these two vesicles and initiates the fusion. Our results reveal that innate immunity triggers a unique modification of TRAF3 and the formation of the HBMEC-specific protein complex on BCVs to authenticate the precise recognition and selection of TfR vesicles to fuse with and facilitate bacterial penetration of the BBB.
摘要：
人血脑屏障(BBB)包含单层脑微血管内皮细胞(HBMEC),其保护脑免受血源性病原体的侵害。脑膜炎是最严重的疾病之一，但是引起脑膜炎的主要细菌病原体穿过BBB到达大脑的机制仍然知之甚少。我们发现肺炎链球菌,B组链球菌,和新生儿脑膜炎大肠杆菌通常利用独特的囊泡融合机制搭便车转铁蛋白受体（TfR）胞吞穿过BBB，并在体外人BBB模型和小鼠模型中说明了这一过程的细节。从含细菌的囊泡（BCV）发出的Toll样受体信号在先天免疫调节因子TRAF3的Lys168和Lys181触发K33连接的聚泛素化，然后激活包含鸟嘌呤核苷酸交换因子RCC2的蛋白质复合物的形成。BCV上的小GTP酶RalA和外囊亚复合物I（SCI）。SEC6在SCI中的独特功能，与BCV上的RalA和TfR囊泡上的SNARE蛋白SNAP23直接相互作用，束缚这两个囊泡并启动融合。我们的结果表明，先天免疫触发TRAF3的独特修饰和BCV上HBMEC特异性蛋白复合物的形成，以验证TfR囊泡的精确识别和选择，以与BBB融合并促进细菌渗透。
