Human Ebola outbreaks usually occur abruptly from an unidentified source, which subsequently spreads from person to person. The pathogenicity and high mortality of Ebola virus infection has been noted in many independent outbreaks (Bowen et al., 1977; Centers for Disease Control and Prevention), but the events that lead to the pathogenicity associated with severe disease are unknown. The terminal stages of infection are characterized by fever, hemorrhage and hypotensive shock, with prominent involvement of the reticuloendothelial and mononuclear phagocytic cell systems. Recent reports indicate that immune mechanisms may contribute to Ebola virus pathogene; inflammatory cytokine levels are higher in fatal cases than in infected survivors (Baize et al., 1999; Villinger et al., 1999).

The prominent clinical features of the Zaire ebolavirus infection in the confirmed cases were fever, severe diarrhea, and vomiting, while hemorrhage was less frequent (Baize et al., 2014). Morphological studies on monkeys infected with the Reston subtype of Ebola virus from the 1989 epizootic (Geisbert et al., 1992) and monkeys experimentally infected with the Zaire subtype (Ryabchikova et al., 1994) showed that monocytes/macrophages and fibroblasts might be the preferred sites of virus replication in early stages, whereas other cell types could become involved as the disease progresses. Human monocytes/macrophages in culture are also sensitive to infection, resulting in massive production of infectious virus and cell lysis (Feldmann et al., 1996). Although the studies on infected non-human primates did not identify endothelial cells as sites of massive virus replication, in vitro studies and post mortem observations of human cases clearly demonstrated that endothelial cells of human origin are suitable targets for virus replication (Schnittler et al., 1993; Zaki et al., 1997). Here infection leads to cell lysis, indicating that damage of endothelial cells may be an important pathophysiological parameter during infection.

It has been demonstrated that supernatants of filovirus-infected monocyte/macrophage cultures are capable of increasing paraendothelial permeability in an in vitro model (Feldmann et al., 1996). Examination for mediators in those supernatants revealed increased levels of secreted TNF-alpha, the prototype cytokine of macrophages. These data support the concept of a mediator-induced vascular instability and, thus, increased premeability as a key mechanism for the development of the shock syndrome seen in severe and fatal cases. Thus, the syndrome may be comparable to shock in response to various endogenous and exogenous mediators (Schnittler et al., 1999). The bleeding tendency could be due to endothelial damage caused directly by virus replication as well as indirectly by cytokine-mediated processes. The onset of the bleeding tendency is supported by the loss of the integrity of the endothelium, as demonstrated in tissue and organ culture (Schnittler et al., 1993) as well as in infected animals (Fisher-Hoch et al., 1985) and seems to occur later in infection. The bleeding tendency may be reinforced by a decrease of the bloodstream as a common consequence of shock. The combination of viral replication in endothelial cells and virus-induced cytokine release from monocytes/macrophages may also promote a distinct proinflammatory endothelial phenotype that then triggers the coagulation cascade.