Ebola Virus Disease (EVD), caused by the Ebola virus (EBOV), is a severe illness characterized by case fatality rates up to 90%. The sporadic nature of outbreaks in resource-limited areas has hindered the ability to characterize the pathogenesis of EVD at all stages of infection, but particularly during early host responses. Pathogenesis is often studied in non-human primate (NHP) models of disease that replicate major aspects of human EVD. Typically, NHP exposures utilize a large infectious dose, are carried out through intramuscular or aerosol exposure, and have a fairly uniform disease course. In contrast, here we report our analysis of the host response to EBOV following intranasal exposure. Twelve cynomolgus macaques were infected with 100 plaque forming units of EBOV/Makona through intranasal exposure, and presented with varying time to onset of EVD. We utilized RNA-Sequencing and a newly developed NanoString codeset to monitor the host response via changes in RNA transcripts over time. When individual animal gene expression data were phased based on onset of sustained fever, the first clinical sign of severe disease, mathematical models indicated that interferon stimulated genes (ISGs) appeared as early as 4 days before fever onset. This demonstrates that lethal EVD has a uniform and predictable response to infection regardless of time-to-onset. Furthermore, expression of a subset of genes could predict disease development prior to other host-based indications of infection such as fever.
