Saban Research Institute of Childrens Hospital Los Angeles, Department of Pediatrics, University of Southern California, Los Angeles, CA 90027, USA.
Brain Pathol. 2011 Jul;21(4):389-404. doi: 10.1111/j.1750-3639.2010.00463.x. Epub 2010 Dec 13.
Transmigration of neutrophil [polymorphonuclear neutrophil (PMN)] across the blood-brain barrier (BBB) is a critical event in the pathogenesis of bacterial meningitis. We have shown that IbeA is able to induce meningitic Escherichia coli invasion of brain microvascular endothelial cells (BMECs), which constitutes the BBB. In this report, we provide evidence that IbeA and its receptor, vimentin, play a key role in E. coli-induced PMN transmigration across BMEC. In vitro and in vivo studies indicated that the ibeA-deletion mutant ZD1 was significantly less active in stimulating PMN transmigration than the parent strain E44. ZD1 was fully complemented by the ibeA gene and its product. E. coli-induced PMN transmigration was markedly inhibited by withaferin A, a dual inhibitor of vimentin and proteasome. These cellular effects were significantly stimulated and blocked by overexpression of vimentin and its head domain deletion mutant in human BMEC, respectively. Our studies further demonstrated that IbeA-induced PMN migration was blocked by bortezomib, a proteasomal inhibitor and correlated with upregulation of endothelial ICAM-1 and CD44 expression through proteasomal regulation of NFκB activity. Taken together, our data suggested that IbeA and vimentin contribute to E. coli K1-stimulated PMN transendothelial migration that is correlated with upregulation of adhesion molecule expression at the BBB.
中性粒细胞（多形核中性粒细胞）穿过血脑屏障是细菌性脑膜炎发病机制中的一个关键事件。我们已经表明，IbeA 能够诱导侵袭性大肠杆菌感染脑微血管内皮细胞（BBB 的组成部分）。在本报告中，我们提供的证据表明，IbeA 和它的受体波形蛋白在大肠杆菌诱导的 PMN 通过 BMEC 迁移中起关键作用。体内外研究表明，与亲本菌株 E44 相比，缺失突变株 ZD1 在刺激 PMN 迁移方面的活性显著降低。ZD1 被 ibeA 基因及其产物完全互补。与野生型相比，双抑制剂维替泊芬 A 显著抑制大肠杆菌诱导的 PMN 迁移，维替泊芬 A 是波形蛋白和蛋白酶体的双重抑制剂。人 BMEC 中波形蛋白及其头部结构域缺失突变体的过表达分别显著刺激和阻断了这些细胞效应。我们的研究进一步表明，IbeA 诱导的 PMN 迁移被蛋白酶体抑制剂硼替佐米阻断，与内皮细胞 ICAM-1 和 CD44 表达的上调相关，这是通过蛋白酶体调节 NFκB 活性实现的。综上所述，我们的数据表明，IbeA 和波形蛋白有助于大肠杆菌 K1 刺激的 PMN 跨内皮迁移，这与 BBB 上粘附分子表达的上调相关。
