Effects of Ebola virus glycoproteins on endothelial cell activation and barrier function
Effects of Ebola virus glycoproteins on endothelial cell activation and barrier function
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DOI：
10.1128/jvi.79.16.10442-10450.2005
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发表时间：
2005-08-01
影响因子：
5.4
通讯作者：
Schnittler, HJ
中科院分区：
文献类型：
--
作者：
Wahl-Jensen, VM;Afanasieva, TA;Schnittler, HJ
埃博拉病毒引起严重的出血热，在人类和非人类灵长类动物中具有高死亡率。血管不稳定和失调是严重感染期间的疾病决定性症状。虽然跨膜糖蛋白GP（1，2）已被证明会导致内皮细胞破坏，但可溶性糖蛋白在发病机制中的作用在很大程度上是未知的;然而，假设它们在靶细胞活化和/或内皮渗透性增加方面具有生物学相关性。在这里，我们表明，由埃博拉病毒基质蛋白VP 40和GP（1，2）组成的病毒样颗粒（VLP）能够激活内皮细胞，并诱导屏障功能的降低，如阻抗谱和水力传导率测量所确定的。与此相反，可溶性糖蛋白sGP和δ-肽不激活内皮细胞或改变内皮屏障功能。VLP诱导的屏障功能下降进一步增强了细胞因子肿瘤坏死因子α（TNF-α），这是已知的诱导内皮细胞屏障功能的长期持续下降，并假设在埃博拉病毒的发病机制中发挥关键作用。令人惊讶的是，sGP，而不是δ-肽，诱导用TNF-α治疗后的内皮屏障功能的恢复。我们的研究结果表明，埃博拉病毒GP（1，2）在其颗粒相关的形式介导内皮细胞活化和内皮细胞屏障功能的降低。此外，sGP（埃博拉病毒的主要可溶性糖蛋白）似乎通过保护内皮细胞屏障功能而具有抗炎作用。
Ebola virus causes severe hemorrhagic fever with high mortality rates in humans and nonhuman primates. Vascular instability and dysregulation are disease-decisive symptoms during severe infection. While the transmembrane glycoprotein GP(1,2) has been shown to cause endothelial cell destruction, the role of the soluble glycoproteins in pathogenesis is largely unknown; however, they are hypothesized to be of biological relevance in terms of target cell activation and/or increase of endothelial permeability. Here we show that virus-like particles (VLPs) consisting of the Ebola virus matrix protein VP40 and GP(1,2) were able to activate endothelial cells and induce a decrease in barrier function as determined by impedance spectroscopy and hydraulic conductivity measurements. In contrast, the soluble glycoproteins sGP and Delta-peptide did not activate endothelial cells or change the endothelial barrier function. The VLP-induced decrease in barrier function was further enhanced by the cytokine tumor necrosis factor alpha (TNF-alpha), which is known to induce a long-lasting decrease in endothelial cell barrier function and is hypothesized to play a key role in Ebola virus pathogenesis. Surprisingly, sGP, but not Delta-peptide, induced a recovery of endothelial barrier function following treatment with TNF-alpha. Our results demonstrate that Ebola virus GP(1,2) in its particle-associated form mediates endothelial cell activation and a decrease in endothelial cell barrier function. Furthermore, sGP, the major soluble glycoprotein of Ebola virus, seems to possess an anti -inflammatory role by protecting the endothelial cell barrier function.