Li Frank Q, Tam James P, Liu Ding Xiang
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
Virology. 2007 Sep 1;365(2):435-45. doi: 10.1016/j.virol.2007.04.015. Epub 2007 May 9.
Manipulation of the cell cycle and induction of apoptosis are two common strategies used by many viruses to regulate their infection cycles. In cells infected with coronaviruses, cell cycle perturbation and apoptosis were observed in several reports. However, little is known about how these effects are brought out, and how manipulation of the functions of host cells would influence the replication cycle of coronavirus. In this study, we demonstrate that infection with coronavirus infectious bronchitis virus (IBV) imposed a growth-inhibitory effect on cultured cells by inducing cell cycle arrest at S and G(2)/M phases in both p53-null cell line H1299 and Vero cells. This cell cycle arrest was catalyzed by the modulation of various cell cycle regulatory genes and the accumulation of hypophosphorylated RB, but was independent of p53. Proteasome inhibitors, such as lactacystin and NLVS, could bypass the IBV-induced S-phase arrest by restoring the expression of corresponding cyclin/Cdk complexes. Our data also showed that cell cycle arrest at both S- and G(2)/M-phases was manipulated by IBV for the enhancement of viral replication. In addition, apoptosis induced by IBV at late stages of the infection cycle in cultured cells was shown to be p53-independent. This conclusion was drawn based on the observations that apoptosis occurred in both IBV-infected H1299 and Vero cells, and that IBV infection did not affect the expression of p53 in host cells.
调控细胞周期和诱导细胞凋亡是许多病毒用来调节其感染周期的两种常见策略。在感染冠状病毒的细胞中，已有数篇报道观察到细胞周期紊乱和细胞凋亡。然而，对于这些效应是如何产生的，以及宿主细胞功能的调控如何影响冠状病毒的复制周期，我们知之甚少。在本研究中，我们证明感染传染性支气管炎病毒（IBV）可通过诱导p53基因缺失的细胞系H1299和Vero细胞在S期和G(2)/M期发生细胞周期阻滞，从而对培养细胞产生生长抑制作用。这种细胞周期阻滞是由多种细胞周期调控基因的调节和低磷酸化RB的积累所催化的，但与p53无关。蛋白酶体抑制剂，如乳胞素和NLVS，可通过恢复相应细胞周期蛋白/Cdk复合物的表达来绕过IBV诱导的S期阻滞。我们的数据还表明，IBV通过操控S期和G(2)/M期的细胞周期阻滞来增强病毒复制。此外，IBV在培养细胞感染后期诱导的细胞凋亡显示与p53无关。这一结论是基于以下观察得出的：IBV感染的H1299和Vero细胞均发生了凋亡，且IBV感染不影响宿主细胞中p53的表达。
