Comparative pathogenesis of Ebola and Reston virus in humanized mice
Beatriz Escudero-Pérez1,2, Paula Ruibal1, Kristin Hartmann3, Sergio Gómez-Medina1,2, Jürgen Müller-Guhl1,4, Monika Rottstegge1,2, Emily Nelson1,2, Susanne Krasemann3, Estefanía Rodriguez4 and César Muñoz-Fontela1,2
1Bernhard Nocht Institute for Tropical Medicine, Hamburg 20359, Germany; 2German Center for Infection Research (DZIF), Partner Site Hamburg; 3Institute for Neuropathology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany; 4Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg 20251, Germany
Ebolaviruses include five different species with significant differences in virulence. Most prominently, while Ebola virus (EBOV, species Zaire ebolavirus) cause severe disease in humans with high case-fatality rates, Reston virus (RESTV) is considered, despite the few human cases reported, asymptomatic in humans but highly pathogenic for non-human primates.
We have recently established a humanized mouse model (huNSG) that is susceptible to non-adapted EBOV and recapitulates many aspects of human Ebola virus disease including viremia and hepatic failure. We have used this new model to compare the pathogenesis of RESTV and EBOV in a small animal model harboring human hematopoietic cells.
Our findings indicate that, while both viruses could replicate and disseminate in huNSG mice, there were notable differences in pathogenesis. Thus, while 90% of mice infected with EBOV succumbed to infection, we observed for the first time that RESTV killed 40% of infected mice. A closer analysis of RESTV-infected mice revealed that death was mainly associated to infiltration of human cells in the liver, which correlated with high levels of virus replication in this organ and high increase of aspartate aminotransferase (AST) and pro-inflammatory cytokines in blood.
Our data points out that humanized mice can be utilized as a platform for comparative studies on filovirus pathogenesis, and warrants further research on RESTV as a putative human pathogen.