文章基本信息

标题：Autophagic flux without a block differentiates varicella-zoster virus infection from herpes simplex virus infection
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作者：Erin M. Buckingham ; John E. Carpenter ; Wallen Jackson 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：1
页码：256-261
DOI：10.1073/pnas.1417878112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceVaricella-zoster virus (VZV) is an important pathogen, which causes varicella and herpes zoster in humans. In general, there are similarities in virus-host interactions between the alphaherpesviruses. One notable exception is the response to autophagy. VZV infection induces autophagy. This is in contrast to herpes simplex virus (HSV), which has two genes that inhibit autophagy, ICP34.5 and US11; neither is present in the smaller VZV genome. In this study, we found that VZV-induced autophagic flux was not blocked. These results reinforce prior observations showing a proviral effect of autophagy on VZV infectivity and spread. These VZV findings also exhibit similarities with recent data about a requirement for early phase autophagy during Epstein-Barr virus infection, a phylogenetically distant gammaherpesvirus. Autophagy is a process by which misfolded and damaged proteins are sequestered into autophagosomes, before degradation in and recycling from lysosomes. We have extensively studied the role of autophagy in varicella-zoster virus (VZV) infection, and have observed that vesicular cells are filled with >100 autophagosomes that are easily detectable after immunolabeling for the LC3 protein. To confirm our hypothesis that increased autophagosome formation was not secondary to a block, we examined all conditions of VZV infection as well as carrying out two assessments of autophagic flux. We first investigated autophagy in human skin xenografts in the severe combined immunodeficiency (SCID) mouse model of VZV pathogenesis, and observed that autophagosomes were abundant in infected human skin tissues. We next investigated autophagy following infection with sonically prepared cell-free virus in cultured cells. Under these conditions, autophagy was detected in a majority of infected cells, but was much less than that seen after an infected-cell inoculum. In other words, inoculation with lower-titered cell-free virus did not reflect the level of stress to the VZV-infected cell that was seen after inoculation of human skin in the SCID mouse model or monolayers with higher-titered infected cells. Finally, we investigated VZV-induced autophagic flux by two different methods (radiolabeling proteins and a dual-colored LC3 plasmid); both showed no evidence of a block in autophagy. Overall, therefore, autophagy within a VZV-infected cell was remarkably different from autophagy within an HSV-infected cell, whose genome contains two modifiers of autophagy, ICP34.5 and US11, not present in VZV.
关键词：autophagy ; autophagosome ; SCID-mouse ; ICP34.5 ; Epstein–Barr virus