Venezuelan Equine Encephalitis Virus Induces Apoptosis through the Unfolded Protein Response Activation of EGR1.
Venezuelan Equine Encephalitis Virus Induces Apoptosis through the Unfolded Protein Response Activation of EGR1.
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DOI：
10.1128/jvi.02827-15
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发表时间：
2016-01-20
影响因子：
5.4
通讯作者：
Kehn-Hall K
中科院分区：
文献类型：
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作者：
Baer A;Lundberg L;Swales D;Waybright N;Pinkham C;Dinman JD;Jacobs JL;Kehn-Hall K
委内瑞拉马脑炎病毒(VEEV)是一种以前武器化的节肢动物传播病毒，可在动物和人类宿主中引起急性和致命脑炎。在美洲，VEEV和其他脑型虫媒病毒，如东部马脑炎病毒和西尼罗河病毒的传播和传播增加，突显出需要进行研究，以确定病毒性脑脊髓炎的发病机制，以制定新的医学对策。应用RNA测序技术对VEEV特立尼达驴感染的人脑星形细胞瘤U87 MG细胞进行了Poly(A)和mRNAs的RNA测序，以确定宿主-病原体的动态。为了确定VEEV感染后宿主转录组发生的关键变化，在感染后4、8和16h收集样本，并使用Ion Torrent PGM平台获取RNA-Seq数据。观察到干扰素反应、应激反应因子和未折叠蛋白反应成分(UPR)的差异表达。UPR的蛋白激酶RNA样内质网激酶(PERK)臂被激活，因为该途径的关键调控因子激活转录因子4(ATF4)和CHOP(DDIT3)的表达在感染后都发生了变化。转录因子早期生长反应1(Egr1)的表达以PERK依赖的方式诱导。Egr1−/−小鼠胚胎成纤维细胞(MEF)对VEEV诱导的细胞死亡的敏感性低于同基因野生型MEF，表明Egr1调控VEEV感染后的促凋亡途径。Egr1的影响非常重要，因为神经元损伤可能会导致VEEV感染幸存者的长期后遗症。重要的是，甲型病毒是一组临床相关的病毒，由蚊子传播给人类。在严重的情况下，病毒传播的目标是神经元组织，导致严重的和威胁生命的炎症，依赖于病毒与宿主的相互作用。目前，由于对脑炎甲型病毒分子发病机制的不完全了解，目前还没有治疗脑炎甲病毒感染的方法。委内瑞拉马脑炎病毒(VEEV)是一种甲型病毒，在美洲流行，能够感染马和人。在这里，我们利用下一代RNA测序来识别VEEV感染的星形胶质细胞中的差异变化。我们的结果表明，与干扰素和未折叠蛋白反应通路相关的转录本的丰度在感染后发生了变化，表明早期生长反应1(Egr1)参与了VEEV诱导的细胞死亡。
Venezuelan equine encephalitis virus (VEEV) is a previously weaponized arthropod-borne virus responsible for causing acute and fatal encephalitis in animal and human hosts. The increased circulation and spread in the Americas of VEEV and other encephalitic arboviruses, such as eastern equine encephalitis virus and West Nile virus, underscore the need for research aimed at characterizing the pathogenesis of viral encephalomyelitis for the development of novel medical countermeasures. The host-pathogen dynamics of VEEV Trinidad donkey-infected human astrocytoma U87MG cells were determined by carrying out RNA sequencing (RNA-Seq) of poly(A) and mRNAs. To identify the critical alterations that take place in the host transcriptome following VEEV infection, samples were collected at 4, 8, and 16 h postinfection and RNA-Seq data were acquired using an Ion Torrent PGM platform. Differential expression of interferon response, stress response factors, and components of the unfolded protein response (UPR) was observed. The protein kinase RNA-like endoplasmic reticulum kinase (PERK) arm of the UPR was activated, as the expression of both activating transcription factor 4 (ATF4) and CHOP (DDIT3), critical regulators of the pathway, was altered after infection. Expression of the transcription factor early growth response 1 (EGR1) was induced in a PERK-dependent manner. EGR1−/− mouse embryonic fibroblasts (MEFs) demonstrated lower susceptibility to VEEV-induced cell death than isogenic wild-type MEFs, indicating that EGR1 modulates proapoptotic pathways following VEEV infection. The influence of EGR1 is of great importance, as neuronal damage can lead to long-term sequelae in individuals who have survived VEEV infection. IMPORTANCE Alphaviruses represent a group of clinically relevant viruses transmitted by mosquitoes to humans. In severe cases, viral spread targets neuronal tissue, resulting in significant and life-threatening inflammation dependent on a combination of virus-host interactions. Currently there are no therapeutics for infections cause by encephalitic alphaviruses due to an incomplete understanding of their molecular pathogenesis. Venezuelan equine encephalitis virus (VEEV) is an alphavirus that is prevalent in the Americas and that is capable of infecting horses and humans. Here we utilized next-generation RNA sequencing to identify differential alterations in VEEV-infected astrocytes. Our results indicated that the abundance of transcripts associated with the interferon and the unfolded protein response pathways was altered following infection and demonstrated that early growth response 1 (EGR1) contributed to VEEV-induced cell death.