Filovirus-induced endothelial leakage triggered by infected monocytes/macrophages.

Abstract

The pathogenetic mechanisms underlying hemorrhagic fevers are not fully understood, but hemorrhage, activation of coagulation, and shock suggest vascular instability. Here, we demonstrate that Marburg virus (MBG), a filovirus causing a severe form of hemorrhagic fever in humans, replicates in human monocytes/macrophages, resulting in cytolytic infection and release of infectious virus particles. Replication also led to intracellular budding and accumulation of viral particles in vacuoles, thus providing a mechanism by which the virus may escape immune surveillance. Monocytes/macrophages were activated by MBG infection as indicated by tumor necrosis factor alpha (TNF-alpha) release. Supernatants of monocyte/macrophage cultures infected with MBG increased the permeability of cultured human endothelial cell monolayers. The increase in endothelial permeability correlated with the time course of TNF-alpha release and was inhibited by a TNF-alpha specific monoclonal antibody. Furthermore, recombinant TNF-alpha added at concentrations present in supernatants of virus-infected macrophage cultures increased endothelial permeability in the presence of 10 micron H2O2. These results indicate that TNF-alpha plays a critical role in mediating increased permeability, which was identified as a paraendothelial route shown by formation of interendothelial gaps. The combination of viral replication in endothelial cells (H.-J. Schnittler, F. Mahner, D. Drenckhahn, H.-D. Klenk, and H. Feldmann, J. Clin. Invest. 19:1301-1309, 1993) and monocytes/macrophages and the permeability-increasing effect of virus-induced cytokine release provide the first experimental data for a novel concept in the pathogenesis of viral hemorrhagic fever.

• Authors: H Feldmann, H Bugany, F Mahner, H D Klenk, D Drenckhahn, H J Schnittler
• Journal: Journal of virology (J Virol) Vol. 70 Issue 4 Pg. 2208-14 (Apr 1996) ISSN: 0022-538X [Print] United States
• PMID: 8642644 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Oligodeoxyribonucleotides
• Tumor Necrosis Factor-alpha

Topics

• Base Sequence
• Cell Membrane Permeability
• Cells, Cultured
• Endothelium, Vascular (ultrastructure)
• Humans
• Macrophage Activation (immunology)
• Macrophages (immunology, ultrastructure, virology)
• Marburgvirus (pathogenicity, physiology, ultrastructure)
• Molecular Sequence Data
• Monocytes (ultrastructure, virology)
• Oligodeoxyribonucleotides
• Tumor Necrosis Factor-alpha (metabolism)
• Virus Replication