State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, the Chinese Academy of Agricultural Sciences, Harbin, People's Republic of China.
State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, the Chinese Academy of Agricultural Sciences, Harbin, People's Republic of China
J Virol. 2018 Aug 29;92(18). doi: 10.1128/JVI.00529-18. Print 2018 Sep 15.
Apoptosis is a common innate defense mechanism of host cells against viral infection and is therefore suppressed by many viruses, including herpes simplex virus (HSV), via various strategies. A recent study reported the apoptosis of remote uninfected cells during Gallid herpesvirus 1 (GaHV-1) infection, yet little is known about this previously unknown aspect of herpesvirus-host interactions. The aim of the present study was to investigate the apoptosis of uninfected host cells during GaHV-1 infection. The present study used and models, which avoided potential interference by host antiviral immunity, and demonstrated that this GaHV-1-host interaction is independent of host immune responses and important for both the pathological effect of viral infection and early viral dissemination from the primary infection site to distant tissues. Further, we revealed that GaHV-1 infection triggers this process in a paracrine-regulated manner. Using genome-wide transcriptome analyses in combination with a set of functional studies, we found that this paracrine-regulated effect requires the repression of p53 activity in uninfected cells. In contrast, the activation of p53 not only prevented the apoptosis of remote uninfected cells and subsequent pathological damage induced by GaHV-1 infection but also delayed viral dissemination significantly. Moreover, p53 activation repressed viral replication both and , suggesting that dual cell-intrinsic mechanisms underlie the suppression of GaHV-1 infection by p53 activation. This study uncovers the mechanism underlying the herpesvirus-triggered apoptosis of remote host cells and extends our understanding of both herpesvirus-host interactions and the roles of p53 in viral infection. It is well accepted that herpesviruses suppress the apoptosis of host cells via various strategies to ensure sustained viral replication during infection. However, a recent study reported the apoptosis of remote uninfected cells during GaHV-1 infection. The mechanism and the biological meaning of this unexpected herpesvirus-host interaction are unclear. This study uncovers the mechanisms of herpesvirus-triggered apoptosis in uninfected cells and may also contribute to a mechanistic illustration of paracrine-regulated apoptosis induced by other viruses in uninfected host cells.
细胞凋亡是宿主细胞抵抗病毒感染的常见固有防御机制，因此包括单纯疱疹病毒（HSV）在内的许多病毒通过各种策略抑制细胞凋亡。最近的一项研究报告了在禽疱疹病毒 1（GaHV-1）感染过程中，远程未感染细胞的凋亡，但对于疱疹病毒-宿主相互作用的这一未知方面知之甚少。本研究旨在探讨 GaHV-1 感染过程中未感染宿主细胞的凋亡。本研究使用了 和 模型，避免了宿主抗病毒免疫的潜在干扰，并证实了这种 GaHV-1-宿主相互作用独立于宿主免疫反应，对于病毒感染的病理效应和从原发感染部位向远处组织的早期病毒传播都很重要。此外，我们揭示了 GaHV-1 感染以旁分泌调节的方式触发这一过程。通过全基因组转录组分析结合一系列功能研究，我们发现这种旁分泌调节效应需要未感染细胞中 p53 活性的抑制。相反，p53 的激活不仅防止了 GaHV-1 感染引起的远程未感染细胞的凋亡和随后的病理损伤，而且显著延迟了病毒的传播。此外，p53 的激活不仅显著抑制了 GaHV-1 感染的病毒复制，而且抑制了 GaHV-1 感染的病毒复制。 ，表明 p53 激活抑制 GaHV-1 感染的双重细胞内在机制。这项研究揭示了疱疹病毒引发远程宿主细胞凋亡的机制，扩展了我们对疱疹病毒-宿主相互作用以及 p53 在病毒感染中的作用的理解。众所周知，疱疹病毒通过各种策略抑制宿主细胞凋亡，以确保感染过程中病毒的持续复制。然而，最近的一项研究报告了在 GaHV-1 感染过程中远程未感染细胞的凋亡。这种意想不到的疱疹病毒-宿主相互作用的机制和生物学意义尚不清楚。本研究揭示了疱疹病毒诱导未感染细胞凋亡的机制，也可能有助于阐明其他病毒在未感染宿主细胞中诱导旁分泌调节凋亡的机制。
