Filovirus-induced endothelial leakage triggered by infected monocytes/macrophages.
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.
Feldmann
H
H
Institut für Virologie, Philipps-Universität Marburg, Germany.
Bugany
H
H
Mahner
F
F
Klenk
H D
HD
Drenckhahn
D
D
Schnittler
H J
HJ
D001483:Base Sequence; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000648:ultrastructure*; D006801:Humans; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000648:ultrastructure / Q000821:virology*; D029024:Marburgvirus / Q000472:pathogenicity* / Q000502:physiology / Q000648:ultrastructure; D008969:Molecular Sequence Data; D009000:Monocytes / Q000648:ultrastructure / Q000821:virology*; D009838:Oligodeoxyribonucleotides; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014779:Virus Replication
D009838:Oligodeoxyribonucleotides; D014409:Tumor Necrosis Factor-alpha