Comparative pathogenesis of Ebola virus and Reston virus infection in humanized mice

TY - JOUR

T1 - Comparative pathogenesis of Ebola virus and Reston virus infection in humanized mice

AU - Escudero-Pérez, Beatriz

AU - Ruibal, Paula

AU - Rottstegge, Monika

AU - Lüdtke, Anja

AU - Port, Julia R

AU - Hartmann, Kristin

AU - Gómez-Medina, Sergio

AU - Müller-Guhl, Jürgen

AU - Nelson, Emily V

AU - Krasemann, Susanne

AU - Rodríguez, Estefanía

AU - Muñoz-Fontela, César

PY - 2019/11/1

Y1 - 2019/11/1

N2 - Filoviruses of the genus Ebolavirus include 6 species with marked differences in their ability to cause disease in humans. From the highly virulent Ebola virus to the seemingly nonpathogenic Reston virus, case fatality rates can range between 0% and 90%. In order to understand the molecular basis of these differences, it is imperative to establish disease models that recapitulate human disease as faithfully as possible. Nonhuman primates (NHPs) are the gold-standard models for filovirus pathogenesis, but comparative studies are skewed by the fact that Reston virus infection can be lethal for NHPs. Here we used HLA-A2-transgenic, NOD-scid-IL-2γ receptor-knockout (NSG-A2) mice reconstituted with human hematopoiesis to compare Ebola virus and Reston virus pathogenesis in a human-like environment. While markedly less pathogenic than Ebola virus, Reston virus killed 20% of infected mice, a finding that was linked to exacerbated inflammation and viral replication in the liver. In addition, the case fatality ratios of different Ebolavirus species in humans were recapitulated in the humanized mice. Our findings point to humanized mice as a putative model to test the pathogenicity of newly discovered filoviruses, and suggest that further investigations on Reston virus pathogenesis in humans are warranted.

AB - Filoviruses of the genus Ebolavirus include 6 species with marked differences in their ability to cause disease in humans. From the highly virulent Ebola virus to the seemingly nonpathogenic Reston virus, case fatality rates can range between 0% and 90%. In order to understand the molecular basis of these differences, it is imperative to establish disease models that recapitulate human disease as faithfully as possible. Nonhuman primates (NHPs) are the gold-standard models for filovirus pathogenesis, but comparative studies are skewed by the fact that Reston virus infection can be lethal for NHPs. Here we used HLA-A2-transgenic, NOD-scid-IL-2γ receptor-knockout (NSG-A2) mice reconstituted with human hematopoiesis to compare Ebola virus and Reston virus pathogenesis in a human-like environment. While markedly less pathogenic than Ebola virus, Reston virus killed 20% of infected mice, a finding that was linked to exacerbated inflammation and viral replication in the liver. In addition, the case fatality ratios of different Ebolavirus species in humans were recapitulated in the humanized mice. Our findings point to humanized mice as a putative model to test the pathogenicity of newly discovered filoviruses, and suggest that further investigations on Reston virus pathogenesis in humans are warranted.

KW - Animals

KW - Disease Models, Animal

KW - Ebolavirus/pathogenicity

KW - Hemorrhagic Fever, Ebola/pathology

KW - Humans

KW - Mice

KW - Mice, Inbred NOD

KW - Mice, SCID

KW - Mucous Membrane/virology

KW - Viral Load

KW - Virus Replication

U2 - 10.1172/jci.insight.126070

DO - 10.1172/jci.insight.126070

M3 - SCORING: Journal article

C2 - 31550241

VL - 4

JO - JCI INSIGHT

JF - JCI INSIGHT

SN - 2379-3708

IS - 21

ER -