Even though the topic is still under discussion, bats are proposed zoonotic reservoirs of ebolaviruses. The evidence comes from detection of virus RNA in wild bats and from the fact that other filoviruses have been successfully isolated from bats. Experimental evidence also demonstrates that Ebola virus cannot successfully establish infection in bats and inbred laboratory mice. Why do ebolaviruses cause severe disease in some species but not others? This is the central research question of our proposal, and it is paramount to understand pathogenesis of ebolaviruses and perhaps other zoonotic viruses. In addition, it is essential to determine ebolavirus-specific pathophysiology mechanisms across species. There are five different species of Ebola virus (EBOV, Sudan, Tai Forest, Bundingbuyo and Reston virus), however, in terms of pathogenicity and lethality, they are very different between them. The mechanisms responsible of these differences have still not been identified. For public health reasons as well as to determine the need for vaccines and therapeutics it is important to understand pathogenesis of these viruses in comparison with EBOV
IMPORTANCE FOR SOCIETY
Despite their importance as human pathogens the epidemiology of ebolavirus outbreaks is poorly understood. Most studies indicate that most human outbreaks are initiated by a single spillover event followed by human-to-human transmission. This was for example the origin of the current outbreak of Ebola virus disease (EVD) in West Africa. In addition to humans, non-human primates (NHPs), pigs and forest antelopes are known to be susceptible to infection with ebolaviruses and show different degrees of susceptibility. In both NHPs and humans, EBOV cause a systemic disease characterized by fever, viremia, coagulation abnormalities and a multiorgan failure that resembles septic shock. Why are these viruses so pathogenic for humans and NHPs and not for other species? This is the central question of our proposal. To address this question, our proposal included the development of an 'in vivo' system to test specoes-specific pathogenicity. This system is based on the idea that severely immunodeficient mice cannot reject xenotransplants, and therefore, can be reconstituted with bone marrow progenitor cells from other species. The importance of our project for society thus is based on two milestones: 1) It provides a system to test ebolavirus pathogenicity across species. 2) It provides a system to test the pathogenicity of unknown viruses in a human-like in vivo system.
OVERALL OBJECTIVES
In order to understand Ebola virus pathogenesis we have developed a xenochimeric mice in which its hematopoietic system has been replaced with a donor species (bat and human hematopoietic system) in order to:
(i) Study species-specific susceptibility to EBOV infection (WP1)
a. species specific susceptibility to EBOV infection
b. Kinetics of EBOV infection and target cells
(ii) Determine ebolavirus-specific pathophysiology mechanisms across species (WP2)
a. Evaluation of Reston and Tai Forest pathogenicity virus in humanized mice
b. Dissection of Ebolavirus pathogenesis in huNSG mice
