Elucidating variations in the nucleotide sequence of Ebola virus associated with increasing pathogenicity

Stuart D Dowall,Cyril Empig,John Kenny,Julian A Hiscox,David A Matthews,Kara Corbin-Lickfett,Neil Hall,Kyle Schlunegger,Miles W Carroll,Christiane Hertz-Fowler,Irene Taylor,Roger Hewson,Isabel García-Dorival,John N Barr

doi:10.1186/s13059-014-0540-x

Abstract

BackgroundEbolaviruses cause a severe and often fatal haemorrhagic fever in humans, with some species such as Ebola virus having case fatality rates approaching 90%. Currently, the worst Ebola virus outbreak since the disease was discovered is occurring in West Africa. Although thought to be a zoonotic infection, a concern is that with increasing numbers of humans being infected, Ebola virus variants could be selected which are better adapted for human-to-human transmission.ResultsTo investigate whether genetic changes in Ebola virus become established in response to adaptation in a different host, a guinea pig model of infection was used. In this experimental system, guinea pigs were infected with Ebola virus (EBOV), which initially did not cause disease. To simulate transmission to uninfected individuals, the virus was serially passaged five times in naïve animals. As the virus was passaged, virulence increased and clinical effects were observed in the guinea pig. An RNAseq and consensus mapping approach was then used to evaluate potential nucleotide changes in the Ebola virus genome at each passage.ConclusionsUpon passage in the guinea pig model, EBOV become more virulent, RNA editing and also coding changes in key proteins become established. The data suggest that the initial evolutionary trajectory of EBOV in a new host can lead to a gain in virulence. Given the circumstances of the sustained transmission of EBOV in the current outbreak in West Africa, increases in virulence may be associated with prolonged and uncontrolled epidemics of EBOV.

Highlights

Ebolaviruses cause a severe and often fatal haemorrhagic fever in humans, with some species such as Ebola virus having case fatality rates approaching 90%
At passage two several animals that met humane clinical endpoints displayed symptoms of hypothermia prior to Results and discussion In order to investigate how the Ebola virus (EBOV) genome changes with increasing pathogenicity, a forced evolution model was used in which EBOV was sequentially passaged in vivo using a guinea pig model of infection
EBOV is initially non-pathogenic in guinea pigs, but becomes more virulent and adapted to replicating in this host [16,17]

Summary

Introduction

Ebolaviruses cause a severe and often fatal haemorrhagic fever in humans, with some species such as Ebola virus having case fatality rates approaching 90%. Ebola virus (EBOV) causes severe haemorrhagic fever in humans and non-human primates. Due to the high mortality rate, potential transmission from person-to-person contact and the lack of approved vaccines or anti-viral therapies, EBOV is classified as a hazard group 4 pathogen. EBOV has the highest case fatality rate (up to 90%) while Reston virus (RESTV) is not pathogenic for humans. RESTV can cause viral haemorrhagic fever in non-human primates and illustrates the potential zoonotic. The combination and action of the Ebola virus gene products and their interactions with the host cell contribute to the severe haemorrhagic fever (see for example [6])

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Results

Conclusion