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Pathogenesis of Ebola Hemorrhagic Fever in Primate Models In Vivo and In Vitro

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Technical Report

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Uniformed Services University Of The Health Sciences Bethesda United States

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Ebola virus EBOV causes severe hemorrhagic fever HF with high mortality in humans and nonhuman primates. Despite progress made during the last decade to identify key modulators of EBOV pathogenesis, cultural mores, and a range of logistical problems, have hindered the systematic pathogenetic analysis of human EBOV infections. Nonhuman primate models of EBOV HF were developed, but with few exceptions, previous investigations examined animals naturally infected or killed when moribund, and shed little light on the pathogenesis of infection during times before death. In this study, we investigated the processes triggering the coagulation abnormalities characteristic of primate EBOV infections and attempted to identify the sequence of key morphologic, virologic, and inflammatory events. This study examined tissues of 21 nonhuman primates over time and also temporally evaluated EBOV infection of primary human monocytesmacrophages PHM and endothelial cells in vitro. Results showed that tissue factor plays an important role in triggering the hemorrhagic complications that characterize EBOV infections, and dysregulation of protein C exacerbates disease. Increased levels of TF were associated with lymphoid macrophages, while analysis of peripheral blood mononuclear cell RNA showed increased tissue factor transcripts by day. Analysis of PHM RNA at 1, 24, and 48 hours showed increased tissue factor transcripts while levels of tissue factor protein were dramatically increased by day 2. A rapid drop in plasma protein C levels was evident in all monkeys by day 2. Moreover, replication of EBOV in endothelial cells was not consistently observed until the latter stages of disease, well after the onset of disseminated intravascular coagulation, suggesting that the characteristic coagulation abnormalities are not the direct result of EBOV-induced cytolysis of endothelial cells.

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