Ebola Virus Disease in Mice with Transplanted Human Hematopoietic Stem Cells

Abstract

The development of treatments for Ebola virus disease (EVD) has been hampered by the lack of small-animal models that mimick human disease. Here we show that mice with transplanted human hematopoetic stem cells reproduce features typical of EVD. Infection with Ebola virus was associated with viremia, cell damage, liver steatosis, signs of hemorrhage, and high lethality. Our study provides a small-animal model with human components for the development of EVD therapies.

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).…”

Humanized Mice as Unique Tools for Human-Specific Studies

“…These inventions cascaded into a series of immunodeficient mice and their variants (BRG, NOG, NRG) (Ali et al 2012; Grover et al 2017; Ishikawa et al 2005; Katano et al 2014; Koboziev et al 2015; Shultz et al 2005) being innovated which enabled in-depth analysis in research areas, such as human hematopoiesis (Rongvaux et al 2011; Yong et al 2016), innate and adaptive immunity (Brehm et al 2010; Pearson et al 2008), autoimmunity (Gunawan et al 2017; Viehmann Milam et al 2014), infectious disease (Keng et al 2015; Lüdtke et al 2015; Wege et al 2012), cancer biology (Chang et al 2015; Her et al 2017; Morton et al 2016), and GvHD (King et al 2008; Kirkiles-Smith et al 2009; Zhao et al 2015), in-turn, facilitating the development of therapeutic agents and novel vaccines. An overview of genotypic and physiological characteristics of each model is outlined in Tables 1 and 2.…”

Ebola Virus Replication and Disease Without Immunopathology in Mice Expressing Transgenes to Support Human Myeloid and Lymphoid Cell Engraftment

“…However, it remains unclear what aspects of humanization in current Hu-Mouse models contribute to clinical disease. WT-EBOV infection of Hu-NSG-A2 (which express the HLA-A2.1 transgene) and NSG-BLT (which are transplanted with human bone marrow, liver, and thymus) HuMice caused severe weight loss, variable time to death, and pathological changes consistent with EVD [21, 22]. However, despite extensive virus replication and up to approximately 67% lethality in intramuscularly inoculated SGM3 HuMice, we did not observe the hallmarks of pathology associated with severe EVD in humans and NHP and rodent models, such as severe inflammation, hepatocyte necrosis, and lymphocyte apoptosis [11, 15, 28].…”

“…Engraftment levels in HuMice have been proposed to contribute to EVD progression and severity [21]. Leukocyte levels in SGM3 HuMice are >20% higher than in previously described models, suggesting that engraftment level may not positively correlate with disease severity in all HuMouse models and that characteristics of disease are associated with complex factors like relative immune cell populations and function.…”

“…To date, wild-type EBOV infection has been characterized in 2 NSG-derived humanized mouse models: NSG mice expressing the human HLA-A2.1 major histocompatibility complex (MHC) class I molecule (Hu-NSG-A2) engrafted with HSC, and NSG mice engrafted with human fetal liver, thymus, and HSC (Hu-NSG-BLT) [21, 22]. Given the importance of the immune response in EBOV pathogenesis, herein we longitudinally characterize infection, human immune cell responses, and pathologic changes in SGM3 HuMice following intraperitoneal or intramuscular inoculation with EBOV-Makona.…”