RGD Reference Report - A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures. - Rat Genome Database

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

Authors: Dinnon, Kenneth H  Leist, Sarah R  Schäfer, Alexandra  Edwards, Caitlin E  Martinez, David R  Montgomery, Stephanie A  West, Ande  Yount, Boyd L  Hou, Yixuan J  Adams, Lily E  Gully, Kendra L  Brown, Ariane J  Huang, Emily  Bryant, Matthew D  Choong, Ingrid C  Glenn, Jeffrey S  Gralinski, Lisa E  Sheahan, Timothy P  Baric, Ralph S 
Citation: Dinnon KH, etal., Nature. 2020 Oct;586(7830):560-566. doi: 10.1038/s41586-020-2708-8. Epub 2020 Aug 27.
RGD ID: 126848773
Pubmed: PMID:32854108   (View Abstract at PubMed)
PMCID: PMC8034761   (View Article at PubMed Central)
DOI: DOI:10.1038/s41586-020-2708-8   (Journal Full-text)

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) pandemic1. Small animal models that recapitulate SARS-CoV-2 disease are needed urgently for rapid evaluation of medical countermeasures2,3. 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 genetics5 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-196.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
IFNL1HumanCOVID-19 amelioratesIMP human protein in a mouse modelRGD 
Ifnl1RatCOVID-19 amelioratesISOIFNL1 (Homo sapiens)human protein in a mouse modelRGD 

Objects Annotated

Genes (Rattus norvegicus)
Ifnl1  (interferon, lambda 1)

Genes (Homo sapiens)
IFNL1  (interferon lambda 1)


Additional Information