Ebolavirus and Marburgvirus comprise two genera of negative-sense single-stranded RNA viruses that cause severe hemorrhagic fevers in humans. Despite considerable research efforts, the molecular events following Ebola virus (EBOV) infection are poorly understood. With the view of identifying host factors that underpin EBOV pathogenesis, we compared the transcriptomes of EBOV-infected human, pig, and bat kidney cells using a transcriptome sequencing (RNA-seq) approach. Despite a significant difference in viral transcription/replication between the cell lines, all cells responded to EBOV infection through a robust induction of extracellular growth factors. Furthermore, a significant upregulation of activator protein 1 (AP1) transcription factor complex members FOS and JUN was observed in permissive cell lines. Functional studies focusing on human cells showed that EBOV infection induces protein expression, phosphorylation, and nuclear accumulation of JUN and, to a lesser degree, FOS. Using a luciferase-based reporter, we show that EBOV infection induces AP1 transactivation activity within human cells at 48 and 72 h postinfection. Finally, we show that JUN knockdown decreases the expression of EBOV-induced host gene expression. Taken together, our study highlights the role of AP1 in promoting the host gene expression profile that defines EBOV pathogenesis.

IMPORTANCE Many questions remain about the molecular events that underpin filovirus pathophysiology. The rational design of new intervention strategies, such as postexposure therapeutics, will be significantly enhanced through an in-depth understanding of these molecular events. We believe that new insights into the molecular pathogenesis of EBOV may be possible by examining the transcriptomic response of taxonomically diverse cell lines (derived from human, pig, and bat). We first identified the responsive pathways using an RNA-seq-based transcriptomics approach. Further functional and computational analysis focusing on human cells highlighted an important role for the AP1 transcription factor in mediating the transcriptional response to EBOV infection. Our study sheds new light on how host transcription factors respond to and promote the transcriptional landscape that follows viral infection.

埃博拉病毒和马尔堡病毒包括两个负型单链RNA病毒，它们会导致人类严重的出血热。尽管进行了大量研究，但对埃博拉病毒（EBOV）感染后的分子事件知之甚少。为了确定支持EBOV发病机理的宿主因子，我们使用转录组测序（RNA-seq）方法比较了EBOV感染的人，猪和蝙蝠肾细胞的转录组。尽管细胞系之间的病毒转录/复制存在显着差异，但所有细胞均通过强烈诱导细胞外生长因子对EBOV感染作出反应。此外，激活蛋白1（AP1）转录因子复合物成员FOS和在允许的细胞系中观察到JUN。针对人类细胞的功能研究表明，EBOV感染会诱导JUN以及FOS的蛋白质表达，磷酸化和核蓄积。使用基于荧光素酶的报道基因，我们显示EBOV感染在感染后48和72 h诱导人细胞内的AP1反式激活活性。最后，我们表明，JUN组合式降低了EBOV诱导的宿主基因表达的表达。综上所述，我们的研究突出了AP1在促进定义EBOV发病机制的宿主基因表达谱中的作用。

重要性关于支持丝状病毒病理生理的分子事件仍然存在许多疑问。通过深入了解这些分子事件，可以显着增强新的干预策略（如接触后治疗）的合理设计。我们认为，通过检查分类学上不同的细胞系（源自人，猪和蝙蝠）的转录组应答，可能会获得有关EBOV分子发病机制的新见解。我们首先使用基于RNA seq的转录组学方法确定了反应途径。针对人细胞的进一步功能和计算分析突显了AP1转录因子在介导对EBOV感染的转录反应中的重要作用。