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.

中文翻译：

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AKT 和 ERK 信号通路的参与促进西尼罗河病毒感染人类神经元细胞

西尼罗河病毒（WNV）是一种重要的嗜神经病毒，导致人类虫媒病毒脑炎和脑膜炎的出现。西尼罗河病毒与信号通路的相互作用在控制西尼罗河病毒感染中发挥着关键作用。我们研究了 AKT 和 ERK 通路在支持 WNV 传播和调节 WNV 感染后炎症反应中的作用。 WNV 在源自人类和小鼠的神经元细胞系中建立了有效的感染。受感染的人神经元细胞中 IL-11 和 TNF-α 的表达显着上调，表明 WNV 感染后引发炎症反应。 WNV 孵化快速激活 AKT (AKT-S6-4E-BP1) 和 ERK (MEK-ERK-p90RSK) 途径的信号级联。用 AKT 抑制剂 MK-2206 或 MEK 抑制剂 U0126 治疗可消除 WNV 诱导的 AKT 或 ERK 激活。 WNV 感染后 24 小时即可检测到 AKT 和 ERK 信号通路的强烈激活，而这种激活在感染后 48 小时被消除。 U0126处理或敲低ERK表达显着增加了WNV RNA水平和病毒滴度，并有效减少了WNV诱导的IL-11产生，表明ERK途径参与了WNV传播和IL-11诱导。 MK-2206 治疗增强了 WNV RNA 复制，同时适度减少了 IL-11 的产生。这些结果表明 AKT 和 ERK 信号通路的参与促进病毒感染，并可能与 WNV 发病机制有关。