Vimentin, a Novel NF-κB Regulator, Is Required for Meningitic Escherichia coli K1-Induced Pathogen Invasion and PMN Transmigration across the Blood-Brain Barrier
Vimentin, a Novel NF-κB Regulator, Is Required for Meningitic Escherichia coli K1-Induced Pathogen Invasion and PMN Transmigration across the Blood-Brain Barrier
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Vimentin 是一种新型 NF-κB 调节剂，是脑膜炎大肠杆菌 K1 诱导的病原体入侵和 PMN 跨血脑屏障迁移所必需的
DOI：
10.1371/journal.pone.0162641
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发表时间：
2016-09-22
期刊：
影响因子：
3.7
通讯作者：
Zhou, Yan-Hong
中科院分区：
文献类型：
--
作者：
Huang, Sheng-He;Chi, Feng;Zhou, Yan-Hong
研究背景NF-κ B活化、病原体侵袭、多形核白细胞（PMN）穿越血脑屏障（BBB）是细菌性脑膜炎的三大特征，但其发病机制尚不清楚。波形蛋白是一种新型NF-κ B调节剂，是主要大肠杆菌K1毒力因子IbeA的主要受体，该因子导致新生儿细菌性败血症和脑膜炎（NSM）的发病机制。我们以前已经表明，IbeA诱导的NF-κ B信号通过其主要受体波形蛋白以及其辅助受体PTB相关剪接因子（PSF）是病原体穿透和白细胞穿越BBB所必需的。这是第一个在体内研究，以证明波形蛋白和相关因素如何有助于致病三联体的细菌性脑膜炎。coli K1诱导的NF-κ B B活化、病原体入侵、白细胞穿越BB B的迁移，现在已经通过使用波形蛋白敲除（KO）小鼠得到证实。在这里介绍的体内研究中，IbeA诱导的NF-κ B B活化，E.在Vim-/-小鼠中，coli K1侵袭和多形核中性粒细胞（PMN）穿过BBB的迁移显著减少。在患有脑膜炎的Vim-/-小鼠中观察到海马齿状回神经元损伤减少。在感染E. coli的Vim-/-小鼠的脑组织中，主要的炎症调节因子α 7 nAChR和几种促进NF-κ B活化的信号分子（p65和p-Cam-KII）显著减少。大肠杆菌脑膜炎。结论：Vimentin是一种新型的NF-κ B调节因子，通过调节NF-κ B信号通路，增加病原体的侵袭、PMN的募集、血脑屏障的通透性和神经元的炎症反应，在脑膜炎感染的宿主防御中起着重要的作用。我们的研究结果为细菌性脑膜炎的致病三联体的病毒依赖性机制提供了第一个证据。
BackgroundNF-kappa B activation, pathogen invasion, polymorphonuclear leukocytes (PMN) transmigration (PMNT) across the blood-brain barrier (BBB) are the pathogenic triad hallmark features of bacterial meningitis, but the mechanisms underlying these events remain largely unknown. Vimentin, which is a novel NF-kappa B regulator, is the primary receptor for the major Escherichia coli K1 virulence factor IbeA that contributes to the pathogenesis of neonatal bacterial sepsis and meningitis (NSM). We have previously shown that IbeA-induced NF-kappa B signaling through its primary receptor vimentin as well as its co-receptor PTB-associated splicing factor (PSF) is required for pathogen penetration and leukocyte transmigration across the BBB. This is the first in vivo study to demonstrate how vimentin and related factors contributed to the pathogenic triad of bacterial meningitis.Methodology/Principal FindingsThe role of vimentin in IbeA(+) E. coli K1-induced NF-kappa B activation, pathogen invasion, leukocyte transmigration across the BBB has now been demonstrated by using vimentin knockout (KO) mice. In the in vivo studies presented here, IbeA-induced NF-kappa B activation, E. coli K1 invasion and polymorphonuclear neutrophil (PMN) transmigration across the BBB were significantly reduced in Vim-/- mice. Decreased neuronal injury in the hippocampal dentate gyrus was observed in Vim-/- mice with meningitis. The major inflammatory regulator alpha 7 nAChR and several signaling molecules contributing to NF-kappa B activation (p65 and p-Cam-KII) were significantly reduced in the brain tissues of the Vim-/- mice with E. coli meningitis. Furthermore, Vim KO resulted in significant reduction in neuronal injury and in a7 nAChR-mediated calcium signaling.Conclusion/SignificanceVimentin, a novel NF-kappa B regulator, plays a detrimental role in the host defense against meningitic infection by modulating the NF-kappa B signaling pathway to increase pathogen invasion, PMN recruitment, BBB permeability and neuronal inflammation. Our findings provide the first evidence for Vim-dependent mechanisms underlying the pathogenic triad of bacterial meningitis.