Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, 77 Puhe Road, Shenbei New District, 110122, Shenyang, China.
Department of Pathology, China Medical University, 77 Puhe Road, Shenbei New District, 110122, Shenyang, China.
Nat Commun. 2018 Jun 12;9(1):2296. doi: 10.1038/s41467-018-04637-3.
Escherichia coli is the leading cause of neonatal Gram-negative bacterial meningitis, but the pathogenesis of E. coli meningitis remains elusive. E. coli penetration of the blood-brain barrier (BBB) is the critical step for development of meningitis. Here, we identify Caspr1, a single-pass transmembrane protein, as a host receptor for E. coli virulence factor IbeA to facilitate BBB penetration. Genetic ablation of endothelial Caspr1 and blocking IbeA-Caspr1 interaction effectively prevent E. coli penetration into the brain during meningitis in rodents. IbeA interacts with extracellular domain of Caspr1 to activate focal adhesion kinase signaling causing E. coli internalization into the brain endothelial cells of BBB. E. coli can invade hippocampal neurons causing apoptosis dependent on IbeA-Caspr1 interaction. Our results indicate that E. coli exploits Caspr1 as a host receptor for penetration of BBB resulting in meningitis, and that Caspr1 might be a useful target for prevention or therapy of E. coli meningitis.
大肠杆菌是新生儿革兰氏阴性细菌性脑膜炎的主要病原体，但大肠杆菌脑膜炎的发病机制仍不清楚。大肠杆菌穿透血脑屏障（BBB）是发生脑膜炎的关键步骤。在这里，我们确定 Caspr1 作为大肠杆菌毒力因子 IbeA 的宿主受体，促进 BBB 穿透。内皮细胞 Caspr1 的基因缺失和阻断 IbeA-Caspr1 相互作用可有效防止啮齿动物脑膜炎期间大肠杆菌穿透大脑。IbeA 与 Caspr1 的细胞外结构域相互作用，激活粘着斑激酶信号通路，导致大肠杆菌内吞进入 BBB 的脑内皮细胞。大肠杆菌可入侵海马神经元，导致依赖于 IbeA-Caspr1 相互作用的细胞凋亡。我们的结果表明，大肠杆菌利用 Caspr1 作为穿透 BBB 的宿主受体，导致脑膜炎，Caspr1 可能是预防或治疗大肠杆菌脑膜炎的有用靶点。
