Tang Wan-Da, Zhu Wei-Yang, Tang Hai-Lin, Zhao Ping, Zhao Lan-Juan
Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Faculty of Naval Medicine, Naval Medical University, 200433, Shanghai, China.
The 16th Student Brigade, College of Basic Medicine, Naval Medical University, 200433, Shanghai, China.
J Virus Erad. 2024 Mar 28;10(1):100368. doi: 10.1016/j.jve.2024.100368. eCollection 2024 Mar.
West Nile virus (WNV) is an important neurotropic virus that accounts for the emergence of human arboviral encephalitis and meningitis. The interaction of WNV with signaling pathways plays a key role in controlling WNV infection. We have investigated the roles of the AKT and ERK pathways in supporting WNV propagation and modulating the inflammatory response following WNV infection. WNV established a productive infection in neuronal cell lines originated from human and mouse. Expression of IL-11 and TNF-α was markedly up-regulated in the infected human neuronal cells, indicating elicitation of inflammation response upon WNV infection. WNV incubation rapidly activated signaling cascades of AKT (AKT-S6-4E-BP1) and ERK (MEK-ERK-p90RSK) pathways. Treatment with AKT inhibitor MK-2206 or MEK inhibitor U0126 abrogated WNV-induced AKT or ERK activation. Strong activation of AKT and ERK signaling pathways could be detectable at 24 h after WNV infection, while such activation was abolished at 48 h post infection. U0126 treatment or knockdown of ERK expression significantly increased WNV RNA levels and viral titers and efficiently decreased IL-11 production induced by WNV, suggesting the involvement of ERK pathway in WNV propagation and IL-11 induction. MK-2206 treatment enhanced WNV RNA replication accompanied with a moderate decrease in IL-11 production. These results demonstrate that engagement of AKT and ERK signaling pathways facilitates viral infection and may be implicated in WNV pathogenesis.
西尼罗河病毒（WNV）是一种重要的嗜神经病毒，可引发人类虫媒病毒性脑炎和脑膜炎。WNV与信号通路的相互作用在控制WNV感染中起关键作用。我们研究了AKT和ERK通路在支持WNV增殖以及调节WNV感染后炎症反应中的作用。WNV在源自人和小鼠的神经元细胞系中建立了有效的感染。在感染的人类神经元细胞中，IL-11和TNF-α的表达明显上调，表明WNV感染引发了炎症反应。WNV孵育迅速激活了AKT（AKT-S6-4E-BP1）和ERK（MEK-ERK-p90RSK）通路的信号级联反应。用AKT抑制剂MK-2206或MEK抑制剂U0126处理可消除WNV诱导的AKT或ERK激活。在WNV感染后24小时可检测到AKT和ERK信号通路的强烈激活，而在感染后48小时这种激活被消除。U0126处理或ERK表达敲低显著增加了WNV RNA水平和病毒滴度，并有效降低了WNV诱导的IL-11产生，表明ERK通路参与了WNV增殖和IL-11诱导。MK-2206处理增强了WNV RNA复制，同时IL-11产生适度减少。这些结果表明，AKT和ERK信号通路的参与促进了病毒感染，可能与WNV发病机制有关。
