Natural history of Ebola virus disease in rhesus monkeys shows viral variant emergence dynamics and tissue-specific host responses

Ebola virus (EBOV) causes Ebola virus disease (EVD), marked by severe hemorrhagic fever; however, the mechanisms underlying the disease remain unclear. To assess the molecular basis of EVD across time, we performed RNA sequencing on 17 tissues from a natural history study of 21 rhesus monkeys, developing new methods to characterize host-pathogen dynamics. We identified alterations in host gene expression with previously unknown tissue-specific changes, including downregulation of genes related to tissue connectivity. EBOV was widely disseminated throughout the body; using a new, broadly applicable deconvolution method, we found that viral load correlated with increased monocyte presence. Patterns of viral variation between tissues differentiated primary infections from compartmentalized infections, and several variants impacted viral fitness in a EBOV/Kikwit minigenome system, suggesting that functionally significant variants can emerge during early infection. This comprehensive portrait of host-pathogen dynamics in EVD illuminates new features of pathogenesis and establishes resources to study other emerging pathogens. [Display omitted] •Ebola virus disseminates quickly and widely, likely mediated by infected monocytes•Emerging viral variation impacts fitness and identifies compartmentalized infections•Host-transcriptional signatures identify changes in vasculature-related genes•Temporal deconvolution of bulk transcriptomes improves cell abundance estimates Normandin et al. explored temporal and spatial host-pathogen dynamics in Ebola virus disease through a natural history study in rhesus monkeys. Bulk transcriptomics of over 400 samples highlighted clinically relevant changes in host gene expression and the emergence of viral mutations that were specific to individual tissues.