Ebolaviruses comprise five virus species of which at least three are highly pathogenic for humans. Other mammalian species such as non-human primates, forest antelopes and pigs are susceptible to ebolavirus infection with different degree of severity. However, bats and laboratory mice are entirely resistant to ebolaviruses. Why do ebolaviruses cause severe disease in some species but not others? This question, which is paramount to understand ebolavirus pathogenesis is the central question of our proposal. To address it, we will build on technology developed by the host laboratory to develop xenochimeric mice, that is, severely immunodeficient mice whose hematopoietic system has been replaced with another from a donor species (e. g. bats, monkeys or humans). This novel in vivo system will allow us to investigate the kinetics of ebolavirus infection across species and to dissect the mechanisms responsible for pathogenicity.