Long Xubing, Li Yuqing, Yang Mengtian, Huang Lu, Gong Weijie, Kuang Ersheng
Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, China.
Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
J Virol. 2016 Aug 12;90(17):7880-93. doi: 10.1128/JVI.00999-16. Print 2016 Sep 1.
Recent studies have shown that inflammatory responses trigger and transmit senescence to neighboring cells and activate the senescence-associated secretory phenotype (SASP). Latent Epstein-Barr virus (EBV) infection induces increased secretion of several inflammatory factors, whereas lytic infections evade the antiviral inflammatory response. However, the changes in and roles of the inflammatory microenvironment during the switch between EBV life cycles remain unknown. In the present study, we demonstrate that latent EBV infection in EBV-positive cells triggers the SASP in neighboring epithelial cells. In contrast, lytic EBV infection abolishes this phenotype. BZLF1 attenuates the transmission of paracrine senescence during lytic EBV infection by downregulating tumor necrosis factor alpha (TNF-α) secretion. A mutant BZLF1 protein, BZLF1Δ207-210, that cannot inhibit TNF-α secretion while maintaining viral transcription, fails to block paracrine senescence, whereas a neutralizing antibody against TNF-α is sufficient to restore its inhibition. Furthermore, latent EBV infection induces oxidative stress in neighboring cells, while BZLF1-mediated downregulation of TNF-α reduces reactive oxygen species (ROS) levels in neighboring cells, and ROS scavengers alleviate paracrine senescence. These results suggest that lytic EBV infection attenuates the transmission of inflammatory paracrine senescence through BZLF1 downregulation of TNF-α secretion and alters the inflammatory microenvironment to allow virus propagation and persistence.
The senescence-associated secretory phenotype (SASP), an important tumorigenic process, is triggered and transmitted by inflammatory factors. The different life cycles of Epstein-Barr virus (EBV) infection in EBV-positive cells employ distinct strategies to modulate the inflammatory response and senescence. The elevation of inflammatory factors during latent EBV infection promotes the SASP in uninfected cells. In contrast, during the viral lytic cycle, BZLF1 suppresses the production of TNF-α, resulting in the attenuation of paracrine inflammatory senescence. This finding indicates that EBV evades inflammatory senescence during lytic infection and switches from facilitating tumor-promoting SASP to generating a virus-propagating microenvironment, thereby facilitating viral spread in EBV-associated diseases.
最近的研究表明，炎症反应会触发衰老并将其传递给邻近细胞，并激活衰老相关分泌表型（SASP）。潜伏性爱泼斯坦 - 巴尔病毒（EBV）感染会导致多种炎症因子分泌增加，而裂解性感染则可逃避抗病毒炎症反应。然而，EBV生命周期转换过程中炎症微环境的变化及其作用仍不清楚。在本研究中，我们证明EBV阳性细胞中的潜伏性EBV感染会触发邻近上皮细胞中的SASP。相反，裂解性EBV感染消除了这种表型。BZLF1通过下调肿瘤坏死因子α（TNF-α）分泌来减弱裂解性EBV感染期间旁分泌衰老的传递。一种不能抑制TNF-α分泌但能维持病毒转录的突变型BZLF1蛋白BZLF1Δ207 - 210无法阻断旁分泌衰老，而抗TNF-α中和抗体足以恢复其抑制作用。此外，潜伏性EBV感染会在邻近细胞中诱导氧化应激，而BZLF1介导的TNF-α下调会降低邻近细胞中的活性氧（ROS）水平，并且ROS清除剂可减轻旁分泌衰老。这些结果表明，裂解性EBV感染通过BZLF下调TNF-α分泌来减弱炎症旁分泌衰老的传递，并改变炎症微环境以促进病毒传播和持续存在。
衰老相关分泌表型（SASP）是一个重要的致瘤过程，由炎症因子触发并传递。EBV阳性细胞中爱泼斯坦 - 巴尔病毒（EBV）感染的不同生命周期采用不同策略来调节炎症反应和衰老。潜伏性EBV感染期间炎症因子的升高促进了未感染细胞中的SASP。相反，在病毒裂解周期中，BZLF1抑制TNF-α的产生，导致旁分泌炎症衰老减弱。这一发现表明，EBV在裂解感染期间逃避炎症衰老，并从促进肿瘤的SASP转变为产生病毒传播的微环境，从而促进EBV相关疾病中的病毒传播。
