National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA, USA.
QIAGEN Bioinformatics, Aarhus, Denmark; QIAGEN Bioinformatics, Maryland, USA.
Virology. 2020 Jan 2;539:121-128. doi: 10.1016/j.virol.2019.10.016. Epub 2019 Oct 31.
Venezuelan equine encephalitis virus (VEEV) is a neurotropic virus that causes significant disease in both humans and equines. Here we characterized the impact of VEEV on signaling pathways regulating cell death in human primary astrocytes. VEEV productively infected primary astrocytes and caused an upregulation of early growth response 1 (EGR1) gene expression at 9 and 18 h post infection. EGR1 induction was dependent on extracellular signal-regulated kinase1/2 (ERK1/2) and protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), but not on p38 mitogen activated protein kinase (MAPK) or phosphoinositide 3-kinase (PI3K) signaling. Knockdown of EGR1 significantly reduced VEEV-induced apoptosis and impacted viral replication. Knockdown of ERK1/2 or PERK significantly reduced EGR1 gene expression, dramatically reduced viral replication, and increased cell survival as well as rescued cells from VEEV-induced apoptosis. These data indicate that EGR1 activation and subsequent cell death are regulated through ERK and PERK pathways in VEEV infected primary astrocytes.
委内瑞拉马脑炎病毒（VEEV）是一种嗜神经病毒，可导致人类和马类严重疾病。在这里，我们描述了 VEEV 对调节人原代星形胶质细胞细胞死亡的信号通路的影响。VEEV 可有效感染原代星形胶质细胞，并在感染后 9 和 18 小时引起早期生长反应 1（EGR1）基因表达的上调。EGR1 的诱导依赖于细胞外信号调节激酶 1/2（ERK1/2）和蛋白激酶 R（PKR）样内质网激酶（PERK），但不依赖于 p38 丝裂原活化蛋白激酶（MAPK）或磷酸肌醇 3-激酶（PI3K）信号通路。EGR1 的敲低显著降低了 VEEV 诱导的细胞凋亡，并影响了病毒复制。ERK1/2 或 PERK 的敲低显著降低了 EGR1 基因表达，显著降低了病毒复制，并增加了细胞存活率，以及从 VEEV 诱导的细胞凋亡中拯救了细胞。这些数据表明，在 VEEV 感染的原代星形胶质细胞中，EGR1 的激活和随后的细胞死亡是通过 ERK 和 PERK 通路调节的。
