Abstract
Ebola virus (EBOV) infection in humans and non-human primates (NHPs) is highly lethal, and there is limited understanding of the mechanisms associated with pathogenesis and survival. Here, we describe a transcriptomic analysis of NHPs that survived lethal EBOV infection, compared to NHPs that did not survive. It has been previously demonstrated that anticoagulant therapeutics increase the survival rate in EBOV-infected NHPs, and that the characteristic transcriptional profile of immune response changes in anticoagulant-treated NHPs. In order to identify transcriptional signatures that correlate with survival following EBOV infection, we compared the mRNA expression profile in peripheral blood mononuclear cells from EBOV-infected NHPs that received anticoagulant treatment, to those that did not receive treatment. We identified a small set of 20 genes that are highly confident predictors and can accurately distinguish between surviving and non-surviving animals. In addition, we identified a larger predictive signature of 238 genes that correlated with disease outcome and treatment; this latter signature was associated with a variety of host responses, such as the inflammatory response, T cell death, and inhibition of viral replication. Notably, among survival-associated genes were subsets of genes that are transcriptionally regulated by (1) CCAAT/enhancer-binding protein alpha, (2) tumor protein 53, and (3) megakaryoblastic leukemia 1 and myocardin-like protein 2. These pathways merit further investigation as potential transcriptional signatures of host immune response to EBOV infection.
Highlights
Ebola virus (EBOV; Filoviridae [1]) infection of humans and non-human primates (NHPs) can cause viral hemorrhagic fever, an acute systemic illness characterized by fever, bleeding diathesis, fulminant shock, and death [2]
Infection of humans and non-human primates (NHPs) with Ebola virus (EBOV) can cause viral hemorrhagic fever, an acute systemic illness which can lead to death
Our results demonstrate that small gene sets and transcriptional regulatory networks can be used to identify individual markers associated with survival following EBOV infection
Summary
Ebola virus (EBOV; Filoviridae [1]) infection of humans and non-human primates (NHPs) can cause viral hemorrhagic fever, an acute systemic illness characterized by fever, bleeding diathesis, fulminant shock, and death [2]. We investigated the hypothesis that there are signatures of gene expression associated with survival in EBOVinfected, anticoagulant-treated NHPs. Immune response pathways play a key role in EBOV pathogenesis. EBOV infection is associated with an early loss of lymphocytes [26,27] and the dysregulation of coagulopathy. This dysregulation of coagulation and subsequent hemorrhage are characteristic of EBOV infection [14,15], and may be due to the fact that immune mediators are over-expressed by monocytes and macrophages, which, along with
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