Disease modeling for Ebola and Marburg viruses

Abstract

The filoviruses Ebola and Marburg are zoonotic agents that are classified as both biosafety level 4 and category A list pathogens. These viruses are pathogenic in humans and cause isolated infections or epidemics of viral hemorrhagic fever, mainly in Central Africa. Their natural reservoir has not been definitely identified, but certain species of African bat have been associated with Ebola and Marburg infections. Currently, there are no licensed options available for either treatment or prophylaxis. Different animal models have been developed for filoviruses including mouse, guinea pig and nonhuman primates. The 'gold standard' animal models for pathogenesis, treatment and vaccine studies are rhesus and cynomolgus macaques. This article provides a brief overview of the clinical picture and the pathology/pathogenesis of human filovirus infections. The current animal model options are discussed and compared with regard to their value in different applications. In general, the small animal models, in particular the mouse, are the most feasible for high biocontainment facilities and they offer the most options for research owing to the greater availability of immunologic and genetic tools. However, their mimicry of the human diseases as well as their predictive value for therapeutic efficacy in primates is limited, thereby making them, at best, valuable initial screening tools for pathophysiology, treatment and vaccine studies.

Fig. 1.

Ebola virus pathogenesis. The final event in severe/lethal cases of Ebola infection is shock, which is caused by several processes that influence each other: systemic viral replication, immune suppression, an increase in vascular permeability and coagulopathy. Infection of primary target cells such as monocytes/macrophages and dendritic cells results in the systemic spread of the virus and differential activation. Monocytes/macrophages are activated to produce pro-inflammatory cytokines and tissue factor, whereas dendritic cell activation is impaired, leading to poor protective immune responses. Although the virus does not infect lymphocytes and natural killer (NK) cells, there is extensive apoptosis in subsets of these cell types. Endothelial cells are activated by pro-inflammatory cytokines and virus particles, leading to increased permeability. Tissue factor expression in monocytes/macrophages induces coagulopathy, which is also able to increase inflammation.