Abstract
The Ebola virus (EBOV) variant Makona (which emerged in 2013) was the causative agent of the largest outbreak of Ebola Virus Disease recorded. Differences in virus-host interactions between viral variants have potential consequences for transmission, disease severity and mortality. A detailed profile of the cellular changes induced by the Makona variant compared with other Ebola virus variants was lacking. In this study, A549 cells, a human cell line with a robust innate response, were infected with the Makona variant or with the Ecran variant originating from the 1976 outbreak in Central Africa. The abundance of viral and cellular mRNA transcripts was profiled using RNASeq and differential gene expression analysis performed. Differences in effects of each virus on the expression of interferon-stimulated genes were also investigated in A549 NPro cells where the type 1 interferon response had been attenuated. Cellular transcriptomic changes were compared with those induced by human respiratory syncytial virus (HRSV), a virus with a similar genome organisation and replication strategy to EBOV. Pathway and gene ontology analysis revealed differential expression of functionally important genes; including genes involved in the inflammatory response, cell proliferation, leukocyte extravasation and cholesterol biosynthesis. Whilst there was overlap with HRSV, there was unique commonality to the EBOV variants.
Highlights
The evolution of Ebolaviruses of varying pathogenicity complicates assessment of the public health significance of novel filoviruses
The possibility remains that infection with the Makona variant may activate or suppress different gene expression pathways when compared with variants of Ebola virus (EBOV)
A549 cells were chosen for this study because they produce a robust innate response to virus infection and have been used to study the innate cell response to a number of different viruses[11,22,23,24,25], including EBOV26
Summary
The evolution of Ebolaviruses of varying pathogenicity complicates assessment of the public health significance of novel filoviruses. Previous work to elucidate host cell responses induced by different filoviruses and EBOV in vitro and in vivo has revealed changes in the strength of activation observed in molecular pathways during infection[8,9,10]. Reston virus (RESTV) has never caused confirmed disease in humans and direct comparison of RESTV with EBOV identified molecular signatures associated with pathogenic filovirus infection[8]. The profiling of cellular changes elicited by virus infection has been used previously to identify fundamental differences in cellular interactions, which occur between high and low pathogenicity variants. A possible reason for differing pathogenicity observed in RESTV compared with EBOV infection may be reduced capacity to terminate virus replication through destruction of host cells. The aim of this study was to define gene expression signatures associated with the Makona variant of EBOV compared to the 1976 Ecran variant by identifying significantly changed patterns of gene expression using RNAseq
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