Ebola Virus GP Activates Endothelial Cells via Host Cytoskeletal Signaling Factors

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-alpha-mediated activation and was associated with apoptotic ECs disruption. In contrast to TNF-alpha, 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-alpha 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.

Automated summary

This study reveals that Ebola-like particles (VLPs) formed by GP, VP40, and NP activate endothelial cells (ECs) via GP, leading to apoptotic ECs disruption and dysfunction. Compared to TNF-alpha, VLPs induce overexpression of ICAM-1 at later time points. Additionally, focal adhesion kinase inhibitors were found to be potent inhibitors of TNF-alpha and VLPs-mediated ICAM-1 expression.