Sanfilippo Christine M, Blaho John A
Department of Microbiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029-6574, USA.
J Virol. 2006 Jul;80(14):6810-21. doi: 10.1128/JVI.00334-06.
Apoptosis is a highly regulated programmed cell death process which is activated during normal development and by various stimuli, such as viral infection, which disturb cellular metabolism and physiology. That herpes simplex virus type 1 (HSV-1) induces apoptosis but then prevents its killing of infected cells is well-established. However, little is known about the viral factor/event which triggers the apoptotic process. We previously reported that infections with either (i) a temperature-sensitive virus at its nonpermissive temperature which does not inject viral DNA into nuclei or (ii) various UV-inactivated wild-type viruses do not result in the induction of apoptosis (C. M. Sanfilippo, F. N. W. Chirimuuta, and J. A. Blaho, J. Virol. 78:224-239, 2004). This indicates that virus receptor binding/attachment to cells, membrane fusion, virion disassembly/tegument dispersal, virion RNAs, and capsid translocation to nuclei are not responsible for induction and implicates viral immediate-early (IE) gene expression in the process. Here, we systematically evaluated the contribution of each IE gene to the stimulation of apoptosis. Using a series of viruses individually deleted for alpha27, alpha4, and alpha22, we determined that these genes are not required for apoptosis induction but rather that their products play roles in its prevention, likely through regulatory effects. Sole expression of alpha0 acted as an "apoptoxin" that was necessary and sufficient to trigger the cell death cascade. Importantly, results using a recombinant virus which contains a stop codon in alpha0 showed that it was not the ICP0 protein which acted as the apoptotic inducer. Based on these findings, we propose that alpha0 gene expression acts as an initial inducer of apoptosis during HSV-1 infection. This represents the first description of apoptosis induction in infected cells triggered as a result of expression of a single viral gene. Expression of apoptotic viral genes is a unique mechanism through which human pathogens may modulate interactions with their host cells.
细胞凋亡是一种高度受调控的程序性细胞死亡过程，在正常发育过程中以及受到各种干扰细胞代谢和生理功能的刺激（如病毒感染）时被激活。1型单纯疱疹病毒（HSV-1）可诱导细胞凋亡，但随后能阻止其对受感染细胞的杀伤作用，这一点已得到充分证实。然而，对于触发凋亡过程的病毒因子/事件却知之甚少。我们之前报道过，（i）在其非允许温度下感染温度敏感型病毒，该病毒不会将病毒DNA注入细胞核，以及（ii）感染各种紫外线灭活的野生型病毒，均不会导致细胞凋亡的诱导（C.M. Sanfilippo、F.N.W. Chirimuuta和J.A. Blaho，《病毒学杂志》78:224 - 239，2004年）。这表明病毒受体与细胞的结合/附着、膜融合、病毒粒子的解体/包膜分散、病毒粒子RNA以及衣壳向细胞核的转运均与凋亡诱导无关，并提示病毒立即早期（IE）基因表达参与了这一过程。在此，我们系统地评估了每个IE基因对细胞凋亡刺激的贡献。通过使用一系列分别缺失α27、α4和α22基因的病毒，我们确定这些基因并非凋亡诱导所必需，而是其产物可能通过调节作用在阻止细胞凋亡中发挥作用。单独表达α0可作为一种“凋亡毒素”，它是触发细胞死亡级联反应所必需且充分的。重要的是，使用在α0基因中含有终止密码子的重组病毒所获得的结果表明，作为凋亡诱导剂的并非ICP0蛋白。基于这些发现，我们提出α0基因表达在HSV-1感染期间作为细胞凋亡的初始诱导因子。这是首次对因单个病毒基因表达而触发的受感染细胞中凋亡诱导的描述。凋亡病毒基因的表达是人类病原体调节与宿主细胞相互作用的一种独特机制。
