Abstract
The 2013–2016 West Africa Ebola virus (EBOV) epidemic caused by the EBOV-Makona isolate is the largest and longest recorded to date. It incurred over 28,000 infections and ∼11,000 deaths. Early in this epidemic, several mutations in viral glycoprotein (A82V), nucleoprotein (R111C), and polymerase L (D759G) emerged and stabilized. In vitro studies of these new EBOV-Makona isolates showed enhanced fitness and viral replication capacity. However, in vivo studies in mice and rhesus macaques did not provide any evidence of enhanced viral fitness or shedding. Infection with late isolates carrying or early isolates lacking (early) these mutations resulted in uniformly lethal disease in nonhuman primates (NHPs), albeit with slightly delayed kinetics with late isolates. The recent report of a possible reemergence of EBOV from a persistent infection in a survivor of the epidemic highlights the urgency for understanding the impact of genetic variation on EBOV pathogenesis. However, potential molecular differences in host responses remain unknown. To address this gap in knowledge, we conducted the first comparative analysis of the host responses to lethal infection with EBOV-Mayinga and EBOV-Makona isolates using bivariate, longitudinal, regression, and discrimination transcriptomic analyses. Our analysis shows a conserved core of differentially expressed genes (DEGs) involved in antiviral defense, immune cell activation, and inflammatory processes in response to EBOV-Makona and EBOV-Mayinga infections. Additionally, EBOV-Makona and EBOV-Mayinga infections could be discriminated based on the expression pattern of a small subset of genes. Transcriptional responses to EBOV-Makona isolates that emerged later during the epidemic, specifically those from Mali and Liberia, lacked signatures of profound lymphopenia and excessive inflammation seen following infection with EBOV-Mayinga and early EBOV-Makona isolate C07. Overall, these findings provide novel insight into the mechanisms underlying the lower case fatality rate (CFR) observed with EBOV-Makona compared to EBOV-Mayinga.
Highlights
Zaire Ebola virus (EBOV) is a single-stranded, negative-sense RNA virus and a member of the Filoviridae family that is responsible for Ebola virus disease (EVD; Sanchez et al, 1993; Bell et al, 2015)
Functional enrichment of these differentially expressed genes (DEGs) using Metascape showed that DEGs downregulated at 4 and 6 days post infection (DPI) enriched to gene ontology (GO) terms related to adaptive immunity (Figure 1B) such as “thymus development” (e.g., AGER, IL7R, and ZAP70) and “T cell activation” (e.g., AKT1, BTLA, and TCF7) (Figure 1B and Supplementary Figure 1A) (Zhou et al, 2019)
DEGs downregulated at 6 DPI played a role in “DNA repair” (e.g., ATM, DNA2, and POLE2) and “cell cycle phase transition” (e.g., BUB1B, CDC27, and CKAP5) (Figure 1B)
Summary
Zaire Ebola virus (EBOV) is a single-stranded, negative-sense RNA virus and a member of the Filoviridae family that is responsible for Ebola virus disease (EVD; Sanchez et al, 1993; Bell et al, 2015). EBOV preferentially infects antigen presenting cells (APCs), notably monocytes, macrophages, and dendritic cells (DCs), that play a critical role in viral dissemination (Geisbert et al, 2003a; Menicucci et al, 2017). The 1976 outbreak of EBOVMayinga and the 1995 outbreak of EBOV-Kikwit resulted in ∼300 cases each and CFRs of ∼90% (Centers for Disease Control and Prevention, 1995a,b; Muyembe-Tamfum et al, 1999; Kuhn et al, 2013; Kaner and Schaack, 2016). The 2013– 2016 West African epidemic caused by the EBOV-Makona isolate resulted in over 28,000 reported cases and a CFR of ∼39% (Kaner and Schaack, 2016; Shoman et al, 2017). Studies in nonhuman primates (NHP), the gold standard animal model to study EBOV pathogenesis, showed comparable clinical disease, infection with EBOV-Makona isolates that emerged late in the epidemic, as a group (Mali and Liberia), resulted in delayed time to euthanasia (Geisbert et al, 2003a, 2015; Marzi et al, 2018; Longet et al, 2020)
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