Humanized Mouse Model of Ebola Virus Disease Mimics the Immune Responses in Human Disease

Abstract

Animal models recapitulating human Ebola virus disease (EVD) are critical for insights into virus pathogenesis. Ebola virus (EBOV) isolates derived directly from human specimens do not, without adaptation, cause disease in immunocompetent adult rodents. Here, we describe EVD in mice engrafted with human immune cells (hu-BLT). hu-BLT mice developed EVD following wild-type EBOV infection. Infection with high-dose EBOV resulted in rapid, lethal EVD with high viral loads, alterations in key human antiviral immune cytokines and chemokines, and severe histopathologic findings similar to those shown in the limited human postmortem data available. A dose- and donor-dependent clinical course was observed in hu-BLT mice infected with lower doses of either Mayinga (1976) or Makona (2014) isolates derived from human EBOV cases. Engraftment of the human cellular immune system appeared to be essential for the observed virulence, as nonengrafted mice did not support productive EBOV replication or develop lethal disease. hu-BLT mice offer a unique model for investigating the human immune response in EVD and an alternative animal model for EVD pathogenesis studies and therapeutic screening.

Post-exposure treatments for Ebola and Marburg virus infections

“…and C.E.M., unpublished data). Humanized mouse models have also recently been developed for Zaire ebolavirus (EBOV) and may have utility for evaluating candidate antivirals 238 .…”

“…and C.E.M., unpublished data). Humanized mouse models have also recently been developed for Zaire ebolavirus (EBOV) and may have utility for evaluating candidate antivirals 238 .Numerous studies show that filovirus infection in NHPs faithfully reproduces known characteristics of human disease 8,9 . Historically, cynomolgus monkeys have been the species most frequently used for preventive vaccine studies, whereas rhesus monkeys have been used almost exclusively for the assessment of post-exposure treatments and therapies.…”

“…This would not have been possible if all preclinical animal studies had to be conducted under GLP or GLP-like conditions. The rVSV-EBOV vaccine is an excellent example of how well-conducted, published, preclinical studies in non-human primates (NHPs) 192,238,285,286 not performed under GLP or GLP-like conditions were used in conjunction with phase I and II clinical data 255,256 to justify conducting clinical trials during the 2013-2016 EBOV epidemic in West Africa. As all preclinical studies in NHPs have been conducted in a small number of BSL-4 facilities in North America, and given the limited number of BSL-4 laboratories that can perform NHP studies worldwide, it does not seem ethically or financially wise to mismanage these resources by performing unnecessary and costly GLP or GLP-like studies, especially under emergency conditions.…”

Recently Identified Mutations in the Ebola Virus-Makona Genome Do Not Alter Pathogenicity in Animal Models

“…As only adapted EBOV variants cause disease in immunocompetent rodents (Banadyga et al, 2016), we chose immunocompromised IFNART −/− mice as the screening model for wild-type isolates and the rhesus macaque model as the confirmatory model. Humanized mice would have been an alternative option for wild-type isolates as several researchers have recently started to evaluate them as small animal disease models for ebolaviruses (Bird et al, 2016; Ludtke et al, 2015; Spengler et al, 2016). However, despite being promising, the current humanized mouse models are not uniform in their biological make-up and still in their infancies in general (Prescott and Feldmann, 2016).…”

Contribution of Human Lung Parenchyma and Leukocyte Influx to Oxidative Stress and Immune System-Mediated Pathology following Nipah Virus Infection

“…Humanized mouse models have been extensively used to study human diseases and virus pathogenesis (21)(22)(23)(24)(25)(26)(27)(28). These models reconstitute the microenvironment of the human lung to evaluate the host response during virus infection in the human lung.…”