A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures

Abstract

Coronaviruses are prone to emergence into new host species most recently evidenced by SARS-CoV-2, the causative agent of the COVID-19 pandemic 1 . Small animal models that recapitulate SARS-CoV-2 disease are desperately needed to rapidly evaluate medical countermeasures (MCMs) 2 , 3 . SARS-CoV-2 cannot infect wildtype laboratory mice due to inefficient interactions between the viral spike (S) protein and the murine ortholog of the human receptor, ACE2 4 . We used reverse genetics 5 to remodel the interaction between S and mACE2 resulting in a recombinant virus (SARS-CoV-2 MA) that could utilize mACE2 for entry. SARS-CoV-2 MA replicated in both the upper and lower airways of both young adult and aged BALB/c mice. Importantly, disease was more severe in aged mice, and showed more clinically relevant phenotypes than those seen in HFH4-hACE2 transgenic mice. We then demonstrated the utility of this model through vaccine challenge studies in immune competent mice with native expression of mACE2. Lastly, we show that clinical candidate interferon (IFN) lambda-1a can potently inhibit SARS-CoV-2 replication in primary human airway epithelial cells in vitro , and both prophylactic and therapeutic administration diminished replication in mice. Our mouse-adapted SARS-CoV-2 model demonstrates age-related disease pathogenesis and supports the clinical use of pegylated IFN lambda-1a treatment in human COVID-19 infections 6 .

Potent mouse monoclonal antibodies that block SARS-CoV-2 infection

“…Our mouse antibodies will not be applicable for use in clinical treatment, if not chimeric and humanized, due to their immunogenicity (Hansel et al, 2010; Reichert et al, 2005). On the other hand, they may be valuable for investigating the mechanism of immune responses to the virus during passive immunization using mouse models for SARS-CoV-2 infection (Bao et al, 2020; Dinnon et al, 2020; Hassan et al, 2020; Israelow et al, 2020; R. D. Jiang et al, 2020; Winkler et al, 2020). They could show stable performance due to lot-to-lot consistency and act as benchmarks for other antibodies and drug developments.…”

Acute SARS-CoV-2 Infection is Highly Cytopathic, Elicits a Robust Innate Immune Response and is Efficiently Prevented by EIDD-2801

“…Animal models are useful in studying highly pathogenic human coronaviruses, the emergence potential of zoonotic coronaviruses, and to evaluate novel inhibitors for their ability to control coronavirus infection [4][5][6][7][8][9][10][11][12][13][14][15] . However, human coronaviruses do not replicate in mice without either extensive adaptation of the virus or genetic modi cation of the host by genetic editing of the receptor or by introducing the individual human receptor genes for each virus [4][5][6][7][8][9][10][11]14,15 . Although existing rodent models have made several important contributions to our understanding of coronavirus infection and pathogenesis, none of these models possess the diverse set of primary human cells present in the human lung that can serve as targets for viral infection 16 .…”

Cell and animal models of SARS-CoV-2 pathogenesis and immunity

“…1) (Corbett et al, 2020a;Zost et al, 2020). Inoculating these mice with Venezuelan equine encephalitis virus that expresses the SARS-CoV-2 Spike protein protected against SARS-CoV-2 infection, and neutralizing antibodies were inversely correlated with lung viral titers (Dinnon et al, 2020). Thus, mouse models are suitable for evaluating vaccine performance against viral replication in the lungs.…”

“…In contrast to golden Syrian hamsters and hACE2 transgenic mice, BALB/c and C57BL/6 mouse strains cannot be readily infected with SARS-CoV-2 human clinical isolates (Dinnon et al, 2020;Imai et al, 2020). Thus, wild-type mice require the modification of the SARS-CoV-2 receptor-binding domain to mediate productive infection and pathogenesis.…”

“…Thus, wild-type mice require the modification of the SARS-CoV-2 receptor-binding domain to mediate productive infection and pathogenesis. Predictive modeling and reverse genetic approaches were leveraged to generate a mouse-adapted SARS-CoV-2 (Dinnon et al, 2020). This virus showed efficient replication in BALB/c mice, with a more pronounced disease phenotype, such as weight loss and lung function, in aged mice compared to young mice.…”