Filovirus-induced endothelial leakage triggered by infected monocytes/macrophages

Abstract

The pathogenetic mechanisms underlying viral 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-␣) 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-␣ release and was inhibited by a TNF-␣specific monoclonal antibody. Furthermore, recombinant TNF-␣ added at concentrations present in supernatants of virus-infected macrophage cultures increased endothelial permeability in the presence of 10 M H 2 O 2. These results indicate that TNF-␣ 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.

Filovirus pathogenesis and immune evasion: insights from Ebola virus and Marburg virus

“…Towards the terminal stage of infection and after the onset of hemorrhagic abnormalities, EBOV replicates in endothelial cells 27 . However, while endothelial cells are thought to play a role in pathogenesis, the molecular mechanisms that affect endothelial function are not yet fully understood 27,[71][72][73][74] .…”

Immunopathology of highly virulent pathogens: insights from Ebola virus

“…Infection of monocytes and macrophages leads to the release of proinflammatory cytokines and chemokines, including tumor necrosis factor, interleukin-1β, macrophage inflammatory protein-1α and reactive oxygen and nitrogen species 11,12 . The expression of these mediators is likely to attract more monocytes and macrophages to the sites of infection and may also attract neutrophils.…”

“…The complete mechanisms leading to endothelium permeability have not been elucidated. Several studies have shown that the virally induced release of inflammatory mediators increases vascular permeability in vitro 11,51 . However, endothelial cells are targets of infection during later stages of the disease and direct virus-induced cytotoxicity of endothelial cells cannot be ruled out as a contributory mechanism for increased hemorrhagic manifestations.…”

C-type lectins do not act as functional receptors for filovirus entry into cells

“…Though these C-type lectins show different specificities, depending on the structures of target glycans, all have been reported to promote filovirus entry. Hepatocytes, dendritic cells, monocytes and macrophages are thought to be the preferred target cells of filoviruses, and infection of these cells is important for hemorrhagic manifestation and immune disorders [20][21][22][23]. Thus, increased infection of these cells might be directly involved in the pathogenesis of filovirus infection [18,24].…”