Abstract
Ebola virus disease (EVD) is a lethal disease caused by the highly pathogenic Ebola virus (EBOV), and its major symptoms in severe cases include vascular leakage and hemorrhage. These symptoms are caused by abnormal activation and disruption of endothelial cells (ECs) whose mediators include EBOV glycoprotein (GP) without the need for viral replication. However, the detailed molecular mechanisms underlying virus–host interactions remain largely unknown. Here, we show that EBOV-like particles (VLPs) formed by GP, VP40, and NP activate ECs in a GP-dependent manner, as demonstrated by the upregulation of intercellular adhesion molecules-1 (ICAM-1) expression. VLPs-mediated ECs activation showed a different kinetic pattern from that of TNF-α-mediated activation and was associated with apoptotic ECs disruption. In contrast to TNF-α, VLPs induced ICAM-1 overexpression at late time points. Furthermore, screening of host cytoskeletal signaling inhibitors revealed that focal adhesion kinase inhibitors were found to be potent inhibitors of ICAM-1 expression mediated by both TNF-α and VLPs. Our results suggest that EBOV GP stimulates ECs to induce endothelial activation and dysfunction with the involvement of host cytoskeletal signaling factors, which represent potential therapeutic targets for EVD.
Highlights
Ebola virus (EBOV), a member of the Filoviridae family, is an enveloped and negativestranded RNA virus that causes severe hemorrhagic fever with high mortality rates in humans and other animals [1,2]
endothelial cells (ECs) were treated with virus-like particles (VLPs) or VLPVP40/NP for 48 h, and the activation of ECs was demonstrated by the upregulation of intercellular adhesion molecules-1 (ICAM-1) expression using immunofluorescence assay
In addition to the induction of ICAM-1 expression, the exposure of ECs to VLPs led to the appearance of cytopathic effects (Figure 1B), which were due to apoptosis, while TNF-α activation of ECs was not associated with apoptosis and subsequent cytopathic effects (Figure 1C–E)
Summary
Ebola virus (EBOV), a member of the Filoviridae family, is an enveloped and negativestranded RNA virus that causes severe hemorrhagic fever with high mortality rates in humans and other animals [1,2]. GP, the transcription of the GP gene generates two nonstructural glycoproteins, the small soluble glycoprotein (ssGP) and the soluble glycoprotein (sGP), through transcriptional editing. The sGP, in turn, generates ∆-peptide as a result of its cleavage [5,6,7]. The cleavage of GP by the cellular metalloprotease TNFα-converting enzyme (TACE) generally occurs during EBOV infection, giving rise to shed GP, which structurally resembles the full-length. Vascular dysregulation leading to an increase in blood vessel permeability, loss of endothelial barrier integrity, and hemorrhage plays an important role in the severity of EBOV infection [1,12,13]
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