脑膜炎大肠杆菌的IbeA诱导多形核细粒细胞穿越血脑屏障的研究
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摘要
多核中性粒细胞（PMN）跨越血脑屏障是细菌性脑膜炎病原发生中的一个关键事件。跨过血脑屏障的迁移-PMN向中枢神经系统的募集是一把“双刃剑”，它不仅是宿主防御系统对抗脑膜炎性细菌病原菌的关键环节，它也会带来显著的中枢神经系统组织损伤；后者导致灾难性的神经系统后遗症。尽管目前疫苗的研发可以降低细菌的感染率，但仍不能完全解除脑膜炎的危害。脑膜炎病理机制方面的研究发现，致病性的脑膜炎性大肠杆菌K1菌株所独有的IbeA蛋白是一个50KDa的膜蛋白,是位于该菌染色体第98分钟处的基因岛-GimA中的一个独特基因所编码的；IbeA作为一侵袭因子，能够诱导大肠杆菌侵入到脑内皮微血管细胞（BMEC）；而正是脑内皮微血管细胞组成了血脑屏障。然而，对于IbeA在PMN跨血脑屏障过程中的作用尚未见报道；本文探索了IbeA在PMN跨血脑屏障迁移中的作用。
通过建立的体外与体内实验模型，分别对ibeA缺失突变体（ZD1）、IbeA蛋白或ibeA基因回补突变体、IbeA蛋白包被的微珠、母本菌株（E44）在人BMEC和大肠杆菌性脑膜炎的小鼠模型中检验了它们对PMN跨内皮迁移至中枢神经系统的诱导能力。ibeA基因缺失突变体未能显著地诱导PMN跨内皮迁移，其所缺失的诱导能力通过基因回补及补充基因产物在体内与体外实验中均可得到修复。据此，我们确定IbeA参与了脑膜炎性E.coli诱导的PMN跨血脑屏障迁移过程。
在确定IbeA参与脑膜炎发生中中性粒细胞向CNS的募集后，对其信号通路与作用机制进行了深入探索。IbeA在大肠杆菌K1菌株与内皮细胞之间的相互作用不是细菌自溶期间毒素分泌的结果。ibeA+大肠杆菌K1菌株诱导的PMN跨过人BMEC迁移以浓度依赖的方式被醉茄素A（WFA）（一种波形蛋白阻断剂）所阻断；人BMEC波形蛋白的过量表达导致大肠杆菌K1诱导的中性粒细胞跨内皮细胞迁移的显著增加，而这一效应没有出现于ibeA缺失突变菌株中。激光共聚焦观察发现正在迁移的多形核粒细胞存在于波形蛋白网络中。这意味着波形蛋白参与了IbeA诱导的PMN以跨细胞路径的迁移。
为了到达感染位点，白细胞需要粘附到血管壁，跨内皮层迁移和浸润到下层组织中去。白细胞迁移研究大多是在肺部及皮肤内皮细胞等非血脑屏障体系中，我们对血脑屏障体系的粘附现象进行了进一步探索。研究发现完整的大肠杆菌K1菌株、和无LPS污染的IbeA蛋白都能够强烈地诱导人BMEC的ICAM-1和CD44的表达，IbeA能够以浓度和时间依赖的方式明显地诱导PMN向人BMEC的粘附。人BMEC中的波形蛋白过量表达可增强ICAM-1和CD44表达的上调，而波形蛋白头部区域缺失的BMEC细胞上ICAM-1和CD44表达减弱。通过3种脂阀破坏剂对BMEC的脂阀进行不同程度的破坏之后，剂量不同均带来了不同的PMN跨BMEC迁移降低，这意味着脂阀/细胞膜穴样内陷的完整与脑膜炎性大肠杆菌诱导的中性粒细胞跨脑部内皮细胞的迁移呈正相关。
最后对IbeA蛋白通过生物信息学方法分析其结构，未能找到任何保守的结构域。因此在预测的IbeA蛋白的二级结构基础上，将其分成了F1-F4四个片段；进行克隆与体外表达纯化之后，对其功能进行了鉴定。结果发现GST-F1-IbeA、GST-F2-IbeA与GST-F4-IbeA不具备诱导PMN跨脑内皮迁移的能力，而GST-F3-IbeA诱导PMN迁移的能力可与IbeA蛋白持平。这意味着GST-F3-IbeA片段为IbeA蛋白的功能性片段，而271至370这一段氨基酸序列是IbeA蛋白诱导PMN跨BMEC迁移的关键功能所在。
本文通过对脑膜炎大肠杆菌K1菌株-大脑微血管内皮细胞-多核白细胞三者相互作用的通路与分子机制的研究，为新生儿大肠杆菌性脑膜炎的病原发生学与治疗学提供新的视点。
Transmigration of neutrophil (PMN) across the blood-brain barrier (BBB) is a criticalevent in the pathogenesis of bacterial meningitis. However, as a “double-edge sword”, therecruitment of PMN into the CNS by transmigration across the BBB is not only crucial forhost defense against meningitic bacterial pathogens, but it is also responsible for significantCNS tissue damage, which results in devastating neurologic sequelae. Although thedevelopment of vaccines could reduce the rate of infection, but this cannot eliminatemeningitis completely. Research on bacterial pathogenecity has identified an importantvirulence factor, IbeA, that contributes to E. coli K1invasion of both intestinal epithelial cellsand BMEC both in vitro and in vivo, and BMEC is the major component of theblood-brain-barrier. The ibeA gene is a unique sequence on the GimA genetic island, onlypresent in pathogenic E. coli K1strains. However, little is know about the role of IbeA inPMN transmigration across the BBB. In this study, we investigate whether and how IbeA isinvolved in the process of PMN transmigration across the BBB.
A number of in vitro and in vivo experiment models were constructed. The ability ofthe ibeA-deletion mutant strain ZD1, the ibeA gene restored-mutant, purified IbeA protein,IbeA protein coated beads, and the parent strain E44to induce PMN transmigration acrossthe brain endothelial to CNS was investigated. It was found that the ibeA-deletion mutantstrain ZD1was significantly less active in stimulating PMN transmigration than the parentstrain E44, ZD1was fully complemented by the ibeA gene or its product both in vitro and invivo. The results indicate that IbeA contributes to PMN transmigration across the BBB.
After showing the involvement of IbeA in the recruitment of neutrophil to CNS duringmeningitis, the signal transduction and its molecular mechanism was investigated further.The interaction between ibeA+E. coli strains and brain endothelial cells was not resultedfrom the toxin secretion during the autolysis of bacteria. The transmigration of PMN acrossBMECs stimulated by ibeA+E. coli strains was blocked by WFA, an inhibitor on vimentin,in a dose-dependent manner. The overexpression of vimentin on human BMECs led to agreat increase of E. coli-induced neutrophil across of brain endothelial cells, and thisphenomenon did not occur to the ibeA-deletion mutant strain. The transmigrating neutrophilwas found in the net of vimentin under the confocal immunofluoresecence microscopy. Allthese indicate that vimentin contributes to the traversal of PMN across brain endothelialsstimulated by IbeA.
In order to migrate to the site of infection, the leukocytes need to adhere to the blood vascular, transendothelially migrate and penetrate into the inner tissue. Previous studies ontransmigration of PMN across the BBB have been performed only to bacterial meningitiscaused by Meningococcus, Pneumococcus and Group B Streptococcus. On the other hand, E.coli-induced adhesive interactions between transmigrating leukocytes and pulmonaryendothelial cells are well understood. ICAM-1and CD44play a role in the leukocytetransmigration process during E. coli pneumonia. However, there are no in vitro and in vivostudies to date that focus on the PMN-brain endothelial cell interactions in response tomeningitic E. coli K1and its virulence factors. Surface adhesion molecules ICAM-1andCD44were upregulated after exposure of the endothelial monolayer to intact E. coli, orpurified IbeA (decontaminated with LPS). The adhesion of PMN to human BMEC wasaffected by IbeA protein in dose and time-course dependent manner. The upregulation ofICAM-1and CD44was increased by overexpression of vimentin on human BMEC anddecreased by deletion of the vimentin head domain. Three lipid rafts detergents were used inthe study of PMN migration, and all of them reduced the ration of PMN transmigration acrossBMEC in a dose-dependent manner. This suggested that there is a relationship between thecomplicity of lipid rafts/caveolae and neutrophil transmigration across BMEC in response tomeningitic E. coli.
Finally, the molecular structure of IbeA protein was analyzed with bioinformatics tools,and no conserved domain was found in the secondary structure. On the basis of the predictedsecondary structure, ibeA was subcloned into four different fragments. Each fragment wasexpressed and proteins purified. It was found, by in vitro PMN transmigration assays, that F1,F2and F4-IbeA proteins did not have the ability to induce PMN transmigration across BMEC,but F3-IbeA did. This result suggested that F3-IbeA is the functional fragment of the IbeAprotein, and the sequence of amino acid from281to370is critical for IbeA to induced PMNtransmigration across BMEC.
通过建立的体外与体内实验模型，分别对ibeA缺失突变体（ZD1）、IbeA蛋白或ibeA基因回补突变体、IbeA蛋白包被的微珠、母本菌株（E44）在人BMEC和大肠杆菌性脑膜炎的小鼠模型中检验了它们对PMN跨内皮迁移至中枢神经系统的诱导能力。ibeA基因缺失突变体未能显著地诱导PMN跨内皮迁移，其所缺失的诱导能力通过基因回补及补充基因产物在体内与体外实验中均可得到修复。据此，我们确定IbeA参与了脑膜炎性E.coli诱导的PMN跨血脑屏障迁移过程。
在确定IbeA参与脑膜炎发生中中性粒细胞向CNS的募集后，对其信号通路与作用机制进行了深入探索。IbeA在大肠杆菌K1菌株与内皮细胞之间的相互作用不是细菌自溶期间毒素分泌的结果。ibeA+大肠杆菌K1菌株诱导的PMN跨过人BMEC迁移以浓度依赖的方式被醉茄素A（WFA）（一种波形蛋白阻断剂）所阻断；人BMEC波形蛋白的过量表达导致大肠杆菌K1诱导的中性粒细胞跨内皮细胞迁移的显著增加，而这一效应没有出现于ibeA缺失突变菌株中。激光共聚焦观察发现正在迁移的多形核粒细胞存在于波形蛋白网络中。这意味着波形蛋白参与了IbeA诱导的PMN以跨细胞路径的迁移。
为了到达感染位点，白细胞需要粘附到血管壁，跨内皮层迁移和浸润到下层组织中去。白细胞迁移研究大多是在肺部及皮肤内皮细胞等非血脑屏障体系中，我们对血脑屏障体系的粘附现象进行了进一步探索。研究发现完整的大肠杆菌K1菌株、和无LPS污染的IbeA蛋白都能够强烈地诱导人BMEC的ICAM-1和CD44的表达，IbeA能够以浓度和时间依赖的方式明显地诱导PMN向人BMEC的粘附。人BMEC中的波形蛋白过量表达可增强ICAM-1和CD44表达的上调，而波形蛋白头部区域缺失的BMEC细胞上ICAM-1和CD44表达减弱。通过3种脂阀破坏剂对BMEC的脂阀进行不同程度的破坏之后，剂量不同均带来了不同的PMN跨BMEC迁移降低，这意味着脂阀/细胞膜穴样内陷的完整与脑膜炎性大肠杆菌诱导的中性粒细胞跨脑部内皮细胞的迁移呈正相关。
最后对IbeA蛋白通过生物信息学方法分析其结构，未能找到任何保守的结构域。因此在预测的IbeA蛋白的二级结构基础上，将其分成了F1-F4四个片段；进行克隆与体外表达纯化之后，对其功能进行了鉴定。结果发现GST-F1-IbeA、GST-F2-IbeA与GST-F4-IbeA不具备诱导PMN跨脑内皮迁移的能力，而GST-F3-IbeA诱导PMN迁移的能力可与IbeA蛋白持平。这意味着GST-F3-IbeA片段为IbeA蛋白的功能性片段，而271至370这一段氨基酸序列是IbeA蛋白诱导PMN跨BMEC迁移的关键功能所在。
本文通过对脑膜炎大肠杆菌K1菌株-大脑微血管内皮细胞-多核白细胞三者相互作用的通路与分子机制的研究，为新生儿大肠杆菌性脑膜炎的病原发生学与治疗学提供新的视点。
Transmigration of neutrophil (PMN) across the blood-brain barrier (BBB) is a criticalevent in the pathogenesis of bacterial meningitis. However, as a “double-edge sword”, therecruitment of PMN into the CNS by transmigration across the BBB is not only crucial forhost defense against meningitic bacterial pathogens, but it is also responsible for significantCNS tissue damage, which results in devastating neurologic sequelae. Although thedevelopment of vaccines could reduce the rate of infection, but this cannot eliminatemeningitis completely. Research on bacterial pathogenecity has identified an importantvirulence factor, IbeA, that contributes to E. coli K1invasion of both intestinal epithelial cellsand BMEC both in vitro and in vivo, and BMEC is the major component of theblood-brain-barrier. The ibeA gene is a unique sequence on the GimA genetic island, onlypresent in pathogenic E. coli K1strains. However, little is know about the role of IbeA inPMN transmigration across the BBB. In this study, we investigate whether and how IbeA isinvolved in the process of PMN transmigration across the BBB.
A number of in vitro and in vivo experiment models were constructed. The ability ofthe ibeA-deletion mutant strain ZD1, the ibeA gene restored-mutant, purified IbeA protein,IbeA protein coated beads, and the parent strain E44to induce PMN transmigration acrossthe brain endothelial to CNS was investigated. It was found that the ibeA-deletion mutantstrain ZD1was significantly less active in stimulating PMN transmigration than the parentstrain E44, ZD1was fully complemented by the ibeA gene or its product both in vitro and invivo. The results indicate that IbeA contributes to PMN transmigration across the BBB.
After showing the involvement of IbeA in the recruitment of neutrophil to CNS duringmeningitis, the signal transduction and its molecular mechanism was investigated further.The interaction between ibeA+E. coli strains and brain endothelial cells was not resultedfrom the toxin secretion during the autolysis of bacteria. The transmigration of PMN acrossBMECs stimulated by ibeA+E. coli strains was blocked by WFA, an inhibitor on vimentin,in a dose-dependent manner. The overexpression of vimentin on human BMECs led to agreat increase of E. coli-induced neutrophil across of brain endothelial cells, and thisphenomenon did not occur to the ibeA-deletion mutant strain. The transmigrating neutrophilwas found in the net of vimentin under the confocal immunofluoresecence microscopy. Allthese indicate that vimentin contributes to the traversal of PMN across brain endothelialsstimulated by IbeA.
In order to migrate to the site of infection, the leukocytes need to adhere to the blood vascular, transendothelially migrate and penetrate into the inner tissue. Previous studies ontransmigration of PMN across the BBB have been performed only to bacterial meningitiscaused by Meningococcus, Pneumococcus and Group B Streptococcus. On the other hand, E.coli-induced adhesive interactions between transmigrating leukocytes and pulmonaryendothelial cells are well understood. ICAM-1and CD44play a role in the leukocytetransmigration process during E. coli pneumonia. However, there are no in vitro and in vivostudies to date that focus on the PMN-brain endothelial cell interactions in response tomeningitic E. coli K1and its virulence factors. Surface adhesion molecules ICAM-1andCD44were upregulated after exposure of the endothelial monolayer to intact E. coli, orpurified IbeA (decontaminated with LPS). The adhesion of PMN to human BMEC wasaffected by IbeA protein in dose and time-course dependent manner. The upregulation ofICAM-1and CD44was increased by overexpression of vimentin on human BMEC anddecreased by deletion of the vimentin head domain. Three lipid rafts detergents were used inthe study of PMN migration, and all of them reduced the ration of PMN transmigration acrossBMEC in a dose-dependent manner. This suggested that there is a relationship between thecomplicity of lipid rafts/caveolae and neutrophil transmigration across BMEC in response tomeningitic E. coli.
Finally, the molecular structure of IbeA protein was analyzed with bioinformatics tools,and no conserved domain was found in the secondary structure. On the basis of the predictedsecondary structure, ibeA was subcloned into four different fragments. Each fragment wasexpressed and proteins purified. It was found, by in vitro PMN transmigration assays, that F1,F2and F4-IbeA proteins did not have the ability to induce PMN transmigration across BMEC,but F3-IbeA did. This result suggested that F3-IbeA is the functional fragment of the IbeAprotein, and the sequence of amino acid from281to370is critical for IbeA to induced PMNtransmigration across BMEC.
引文
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