5 years ago

Comparative transcriptomics highlights the role of the AP1 transcription factor in the host response to Ebolavirus.

Boyd V, Dearnley M, Baker ML, Purcell AW, Tachedjian M, Wynne JW, McAuley AJ, Shiell B, Todd S, Woon AP, Klein R, Marsh GA
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 an RNAseq 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 up-regulation of 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 showed that EBOV infection induces AP1 transactivation activity at 48 and 72 hours post infection within human cells. 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.Non-technical summary Many questions remain about the molecular events that underpin filovirus pathophysiology. The rational design of new intervention strategies, such as post-exposure therapeutics, will be significantly enhanced through an in-depth understanding of these molecular events. We believe 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 RNAseq-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 and promote the transcriptional landscape that follows viral infection.

Publisher URL: https://www.ncbi.nlm.nih.gov/pubmed/28931675

DOI: PubMed:28931675

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