Journal Article

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

Choong, Ingrid C., Adams, Lily E., Montgomery, Stephanie A., Hou, Yixuan J., Bryant, Matthew D., Glenn, Jeffrey S., Dinnon, Kenneth H., Sheahan, Timothy P., Martinez, David R., Huang, Emily, Brown, Ariane J., Gully, Kendra L., Baric, Ralph S., West, Ande, Schäfer, Alexandra, Leist, Sarah R., Edwards, Caitlin E., Gralinski, Lisa E., Yount, Boyd L.

2020

Overview

Coronaviruses are prone to transmission to new host species, as recently demonstrated by the spread to humans of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic 1 . Small animal models that recapitulate SARS-CoV-2 disease are needed urgently for rapid evaluation of medical countermeasures 2 , 3 . SARS-CoV-2 cannot infect wild-type laboratory mice owing to inefficient interactions between the viral spike protein and the mouse orthologue of the human receptor, angiotensin-converting enzyme 2 (ACE2) 4 . Here we used reverse genetics 5 to remodel the interaction between SARS-CoV-2 spike protein and mouse ACE2 and designed mouse-adapted SARS-CoV-2 (SARS-CoV-2 MA), a recombinant virus that can use mouse ACE2 for entry into cells. SARS-CoV-2 MA was able to replicate in the upper and lower airways of both young adult and aged BALB/c mice. SARS-CoV-2 MA caused more severe disease in aged mice, and exhibited more clinically relevant phenotypes than those seen in Hfh4 - ACE2 transgenic mice, which express human ACE2 under the control of the Hfh4 (also known as Foxj1 ) promoter. We demonstrate the utility of this model using vaccine-challenge studies in immune-competent mice with native expression of mouse ACE2. Finally, we show that the clinical candidate interferon-λ1a (IFN-λ1a) potently inhibits SARS-CoV-2 replication in primary human airway epithelial cells in vitro—both prophylactic and therapeutic administration of IFN-λ1a diminished SARS-CoV-2 replication in mice. In summary, the mouse-adapted SARS-CoV-2 MA model demonstrates age-related disease pathogenesis and supports the clinical use of pegylated IFN-λ1a as a treatment for human COVID-19 6 . A model in mouse using a species-adapted virus recapitulates features of SARS-CoV-2 infection and age-related disease pathogenesis in humans, and provides a model system for rapid evaluation of medical countermeasures against coronavirus disease 2019 (COVID-19).

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/109 / 13/21 / 14/63 / 38/77 / 631/326/590 / 631/326/596/1296 / 631/326/596/4130 / 64/60 / ACE2 / Age / Age related diseases / Aging - immunology / Angiotensin-Converting Enzyme 2 / Animal models / Animals / Betacoronavirus - drug effects / Betacoronavirus - immunology / Betacoronavirus - pathogenicity / Coronaviridae / Coronavirus Infections - drug therapy / Coronavirus Infections - genetics / Coronavirus Infections - immunology / Coronavirus Infections - prevention & control / Coronaviruses / COVID-19 / COVID-19 Vaccines / Disease Models, Animal / Disease transmission / Epithelial cells / Evaluation / Female / Forkhead Transcription Factors - genetics / Homeopathy / Humanities and Social Sciences / Humans / Immune system / Interferon / Interferon-alpha - administration & dosage / Interferon-alpha - pharmacology / Interferon-alpha - therapeutic use / Interferons - administration & dosage / Interferons - pharmacology / Interferons - therapeutic use / Interleukins - administration & dosage / Interleukins - pharmacology / Interleukins - therapeutic use / Laboratory animals / Male / Materia medica and therapeutics / Mice / Mice, Inbred BALB C / Mice, Transgenic / Middle East respiratory syndrome / Models, Molecular / multidisciplinary / Pandemics - prevention & control / Pathogenesis / Peptidyl-Dipeptidase A - genetics / Peptidyl-Dipeptidase A - metabolism / Phenotypes / Pneumonia, Viral - drug therapy / Pneumonia, Viral - genetics / Pneumonia, Viral - immunology / Pneumonia, Viral - prevention & control / Proteins / Receptors, Virus - genetics / Receptors, Virus - metabolism / Replication / Respiratory diseases / Rodents / SARS-CoV-2 / Science / Science (multidisciplinary) / Severe acute respiratory syndrome coronavirus 2 / Spike protein / Testing / Therapeutics / Therapeutics, Experimental / Transgenic mice / Viral diseases / Viral Vaccines - immunology / Young adults