Venezuelan equine encephalitis virus entry mechanism requires late endosome fort-nation and resists cell membrane cholesterol depletion
Venezuelan equine encephalitis virus entry mechanism requires late endosome fort-nation and resists cell membrane cholesterol depletion
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DOI：
10.1016/j.virol.2005.11.051
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发表时间：
2006-04-10
期刊：
影响因子：
3.7
通讯作者：
Davey, RA
中科院分区：
文献类型：
--
作者：
Kolokoltsov, AA;Fleming, EH;Davey, RA
病毒包膜蛋白决定受体利用率和宿主范围。受体的选择不仅使病毒特异性靶向表达它的细胞，而且还将病毒引导到特定的内体运输途径。破坏贩运可导致病毒感染性的丧失，因为病毒体重定向到非生产性途径。因此，鉴定病毒使用的一种或多种途径对于理解病毒发病机制和开发新的治疗策略是重要的。我们对甲病毒进入的大部分理解都集中在旧世界甲病毒上，如辛德比斯和塞姆利基森林病毒。相比之下，人们对致病性更强的新世界甲病毒的进入途径知之甚少。在这里，我们使用一种新的内容物混合试验，以确定新的世界甲病毒，委内瑞拉马脑炎病毒（VEEV）进入细胞的要求。主要内体运输基因的显性阴性形式的表达表明VEEV必须进入网格蛋白依赖性内吞囊泡以发生膜融合。出乎意料的是，退出点与从早期内涵体离开的旧世界甲病毒不同。相反，VEEV还需要功能性晚期内体。此外，与旧世界病毒不同，VEEV进入对来自细胞膜的胆固醇隔离不敏感，并且可能反映了进入缺乏胆固醇的内吞区室的需要。这表明VEEV与旧世界甲病毒相比所采取的进入途径存在根本差异。(c)2005年爱思唯尔公司All rights reserved.
Virus envelope proteins determine receptor utilization and host range. The choice of receptor not only pen-nits specific targeting of cells that express it, but also directs the virus into specific endosomal trafficking pathways. Disrupting trafficking can result in loss of virus infectivity due to redirection of virions to non-productive pathways. Identification of the pathway or pathways used by a virus is, thus, important in understanding virus pathogenesis mechanisms and for developing new treatment strategies. Most of our understanding of alphavirus entry has focused on the Old World alphaviruses, such as Sindbis and Semliki Forest virus. In comparison, very little is known about the entry route taken by more pathogenic New World alphaviruses. Here, we use a novel contents mixing assay to identify the cellular requirements for entry of a New World alphavirus, Venezuelan equine encephalitis virus (VEEV). Expression of dominant negative forms of key endosomal trafficking genes shows that VEEV must access clathrin-dependent endocytic vesicles for membrane fusion to occur. Unexpectedly, the exit point is different from Old World alphaviruses that leave from early endosomes. Instead, VEEV also requires functional late endosomes. Furthermore, unlike the Old World viruses, VEEV entry is insensitive to cholesterol sequestration from cell membranes and may reflect a need to access an endocytic compartment that lacks cholesterol. This indicates fundamental differences in the entry route taken by VEEV compared to Old World alphaviruses. (c) 2005 Elsevier Inc. All rights reserved.