Cholesterol dependence of Varicella-Zoster virion entry into target cells
Cholesterol dependence of Varicella-Zoster virion entry into target cells
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DOI：
10.1128/jvi.00486-07
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发表时间：
2007-07-01
影响因子：
5.4
通讯作者：
Gershon, A. A.
中科院分区：
文献类型：
--
作者：
Hambleton, S.;Steinberg, S. P.;Gershon, A. A.
吸入的病毒粒子进入气道细胞可能是水痘带状疱疹感染的起始步骤。为了表征病毒进入，我们研究了脂筏和网格蛋白介导的运输所发挥的相对作用。病毒和靶细胞预处理与代理设计扰动选定方面的内吞作用和膜组成，并监测这些扰动对感染性病灶形成的影响。对甲基-β-环糊精（M β CD）和制霉菌素非常敏感，它们通过去除胆固醇破坏脂筏。这些药物以剂量依赖性方式抑制有包膜水痘带状疱疹病毒（VZV）感染，但不抑制细胞相关水痘带状疱疹病毒（VZV）感染，并对靶细胞和病毒膜产生这些作用。M β CD的抑制作用），这可以通过胆固醇补充逆转，在靶细胞暴露于VZV后，作为时间的函数迅速下降，表明病毒感染的早期步骤需要胆固醇。胆固醇消耗没有影响，但是，被认为是病毒结合，此外，有没有减少表面表达或内化的甘露糖6-磷酸受体，这是需要VZV进入。病毒进入是能量依赖性的，并表现出浓度依赖性抑制氯丙嗪，其中，在其他行动，块网格蛋白介导的内吞作用。这些数据表明，膜脂质组成和网格蛋白介导的运输是至关重要的VZV进入。脂筏可能直接促进病毒包膜的完整性，并且在宿主膜中，可能影响内吞作用，引起下游信号传导，和/或促进膜融合。
The entry of inhaled virions into airway cells is presumably the initiating step of varicella-zoster infection. In order to characterize viral entry, we studied the relative roles played by lipid rafts and clathrin-mediated transport. Virus and target cells were pretreated with agents designed to perturb selected aspects of endocytosis and membrane composition, and the effects of these perturbations on infectious focus formation were monitored. Infectivity was exquisitely sensitive to methyl-beta-cyclodextrin (M beta CD) and nystatin, which disrupt lipid rafts by removing cholesterol. These agents inhibited infection by enveloped, but not cell-associated, varicella-zoster virus (VZV) in a dose-dependent manner and exerted these effects on both target cell and viral membranes. Inhibition by M beta CD), which could be reversed by cholesterol replenishment, rapidly declined as a function of time after exposure of target cells to VZV, suggesting that an early step in viral infection requires cholesterol. No effect of cholesterol depletion, however, was seen on viral binding; moreover, there was no reduction in the surface expression or internalization of mannose 6-phosphate receptors, which are required for VZV entry. Viral entry was energy dependent and showed concentration-dependent inhibition by chlorpromazine, which, among other actions, blocks clathrin-mediated endocytosis. These data suggest that both membrane lipid composition and clathrin-mediated transport are critical for VZV entry. Lipid rafts are likely to contribute directly to viral envelope integrity and, in the host membrane, may influence endocytosis, evoke downstream signaling, and/or facilitate membrane fusion.