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

Identifieur interne : 000839 ( Main/Exploration ); précédent : 000838; suivant : 000840

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

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

Source :

RBID : pubmed:32854108

Descripteurs français

English descriptors

Abstract

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.

DOI: 10.1038/s41586-020-2708-8
PubMed: 32854108


Affiliations:

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<name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S" last="Baric">Ralph S. Baric</name>
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<nlm:affiliation>Rapidly Emerging Antiviral Drug Discovery Initiative, University of North Carolina, Chapel Hill, NC, USA. rbaric@email.unc.edu.</nlm:affiliation>
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<wicri:regionArea>Rapidly Emerging Antiviral Drug Discovery Initiative, University of North Carolina, Chapel Hill, NC</wicri:regionArea>
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<name sortKey="Hou, Yixuan J" sort="Hou, Yixuan J" uniqKey="Hou Y" first="Yixuan J" last="Hou">Yixuan J. Hou</name>
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<nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.</nlm:affiliation>
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<name sortKey="Adams, Lily E" sort="Adams, Lily E" uniqKey="Adams L" first="Lily E" last="Adams">Lily E. Adams</name>
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<nlm:affiliation>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC</wicri:regionArea>
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<region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
</placeName>
<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
</affiliation>
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<name sortKey="Gully, Kendra L" sort="Gully, Kendra L" uniqKey="Gully K" first="Kendra L" last="Gully">Kendra L. Gully</name>
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<nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC</wicri:regionArea>
<placeName>
<region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
</placeName>
<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
</affiliation>
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<author>
<name sortKey="Brown, Ariane J" sort="Brown, Ariane J" uniqKey="Brown A" first="Ariane J" last="Brown">Ariane J. Brown</name>
<affiliation wicri:level="4">
<nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC</wicri:regionArea>
<placeName>
<region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
</placeName>
<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
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<author>
<name sortKey="Huang, Emily" sort="Huang, Emily" uniqKey="Huang E" first="Emily" last="Huang">Emily Huang</name>
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<nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC</wicri:regionArea>
<placeName>
<region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
</placeName>
<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
</affiliation>
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<author>
<name sortKey="Bryant, Matthew D" sort="Bryant, Matthew D" uniqKey="Bryant M" first="Matthew D" last="Bryant">Matthew D. Bryant</name>
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<nlm:affiliation>Eiger BioPharmaceuticals, Palo Alto, CA, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Eiger BioPharmaceuticals, Palo Alto, CA</wicri:regionArea>
<placeName>
<region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Choong, Ingrid C" sort="Choong, Ingrid C" uniqKey="Choong I" first="Ingrid C" last="Choong">Ingrid C. Choong</name>
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<nlm:affiliation>Eiger BioPharmaceuticals, Palo Alto, CA, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Eiger BioPharmaceuticals, Palo Alto, CA</wicri:regionArea>
<placeName>
<region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Glenn, Jeffrey S" sort="Glenn, Jeffrey S" uniqKey="Glenn J" first="Jeffrey S" last="Glenn">Jeffrey S. Glenn</name>
<affiliation wicri:level="4">
<nlm:affiliation>Departments of Medicine and Microbiology and Immunology, Stanford University, Stanford, CA, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Departments of Medicine and Microbiology and Immunology, Stanford University, Stanford, CA</wicri:regionArea>
<placeName>
<region type="state">Californie</region>
<settlement type="city">Stanford (Californie)</settlement>
</placeName>
<orgName type="university">Université Stanford</orgName>
</affiliation>
<affiliation wicri:level="2">
<nlm:affiliation>Palo Alto Veterans Administration, Palo Alto, CA, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Palo Alto Veterans Administration, Palo Alto, CA</wicri:regionArea>
<placeName>
<region type="state">Californie</region>
</placeName>
</affiliation>
</author>
<author>
<name sortKey="Gralinski, Lisa E" sort="Gralinski, Lisa E" uniqKey="Gralinski L" first="Lisa E" last="Gralinski">Lisa E. Gralinski</name>
<affiliation wicri:level="4">
<nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC</wicri:regionArea>
<placeName>
<region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
</placeName>
<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
</affiliation>
</author>
<author>
<name sortKey="Sheahan, Timothy P" sort="Sheahan, Timothy P" uniqKey="Sheahan T" first="Timothy P" last="Sheahan">Timothy P. Sheahan</name>
<affiliation wicri:level="4">
<nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC</wicri:regionArea>
<placeName>
<region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
</placeName>
<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
</affiliation>
</author>
<author>
<name sortKey="Baric, Ralph S" sort="Baric, Ralph S" uniqKey="Baric R" first="Ralph S" last="Baric">Ralph S. Baric</name>
<affiliation wicri:level="4">
<nlm:affiliation>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. rbaric@email.unc.edu.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC</wicri:regionArea>
<placeName>
<region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
</placeName>
<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
</affiliation>
<affiliation wicri:level="4">
<nlm:affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. rbaric@email.unc.edu.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC</wicri:regionArea>
<placeName>
<region type="state">Caroline du Nord</region>
<settlement type="city">Chapel Hill (Caroline du Nord)</settlement>
</placeName>
<orgName type="university">Université de Caroline du Nord à Chapel Hill</orgName>
</affiliation>
<affiliation wicri:level="2">
<nlm:affiliation>Rapidly Emerging Antiviral Drug Discovery Initiative, University of North Carolina, Chapel Hill, NC, USA. rbaric@email.unc.edu.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Rapidly Emerging Antiviral Drug Discovery Initiative, University of North Carolina, Chapel Hill, NC</wicri:regionArea>
<placeName>
<region type="state">Caroline du Nord</region>
</placeName>
</affiliation>
</author>
</analytic>
<series>
<title level="j">Nature</title>
<idno type="eISSN">1476-4687</idno>
<imprint>
<date when="2020" type="published">2020</date>
</imprint>
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<keywords scheme="KwdEn" xml:lang="en">
<term>Aging (immunology)</term>
<term>Angiotensin-Converting Enzyme 2 (MeSH)</term>
<term>Animals (MeSH)</term>
<term>Betacoronavirus (drug effects)</term>
<term>Betacoronavirus (immunology)</term>
<term>Betacoronavirus (pathogenicity)</term>
<term>COVID-19 (MeSH)</term>
<term>COVID-19 Vaccines (MeSH)</term>
<term>Coronavirus Infections (drug therapy)</term>
<term>Coronavirus Infections (genetics)</term>
<term>Coronavirus Infections (immunology)</term>
<term>Coronavirus Infections (prevention & control)</term>
<term>Disease Models, Animal (MeSH)</term>
<term>Female (MeSH)</term>
<term>Forkhead Transcription Factors (genetics)</term>
<term>Humans (MeSH)</term>
<term>Interferon-alpha (administration & dosage)</term>
<term>Interferon-alpha (pharmacology)</term>
<term>Interferon-alpha (therapeutic use)</term>
<term>Interferons (administration & dosage)</term>
<term>Interferons (pharmacology)</term>
<term>Interferons (therapeutic use)</term>
<term>Interleukins (administration & dosage)</term>
<term>Interleukins (pharmacology)</term>
<term>Interleukins (therapeutic use)</term>
<term>Male (MeSH)</term>
<term>Mice (MeSH)</term>
<term>Mice, Inbred BALB C (MeSH)</term>
<term>Mice, Transgenic (MeSH)</term>
<term>Models, Molecular (MeSH)</term>
<term>Pandemics (prevention & control)</term>
<term>Peptidyl-Dipeptidase A (genetics)</term>
<term>Peptidyl-Dipeptidase A (metabolism)</term>
<term>Pneumonia, Viral (drug therapy)</term>
<term>Pneumonia, Viral (genetics)</term>
<term>Pneumonia, Viral (immunology)</term>
<term>Pneumonia, Viral (prevention & control)</term>
<term>Receptors, Virus (genetics)</term>
<term>Receptors, Virus (metabolism)</term>
<term>SARS-CoV-2 (MeSH)</term>
<term>Viral Vaccines (immunology)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr">
<term>Animaux (MeSH)</term>
<term>Betacoronavirus (effets des médicaments et des substances chimiques)</term>
<term>Betacoronavirus (immunologie)</term>
<term>Betacoronavirus (pathogénicité)</term>
<term>Facteurs de transcription Forkhead (génétique)</term>
<term>Femelle (MeSH)</term>
<term>Humains (MeSH)</term>
<term>Infections à coronavirus (génétique)</term>
<term>Infections à coronavirus (immunologie)</term>
<term>Infections à coronavirus (prévention et contrôle)</term>
<term>Infections à coronavirus (traitement médicamenteux)</term>
<term>Interféron alpha (administration et posologie)</term>
<term>Interféron alpha (pharmacologie)</term>
<term>Interféron alpha (usage thérapeutique)</term>
<term>Interférons (administration et posologie)</term>
<term>Interférons (pharmacologie)</term>
<term>Interférons (usage thérapeutique)</term>
<term>Interleukines (administration et posologie)</term>
<term>Interleukines (pharmacologie)</term>
<term>Interleukines (usage thérapeutique)</term>
<term>Modèles animaux de maladie humaine (MeSH)</term>
<term>Modèles moléculaires (MeSH)</term>
<term>Mâle (MeSH)</term>
<term>Pandémies (prévention et contrôle)</term>
<term>Peptidyl-Dipeptidase A (génétique)</term>
<term>Peptidyl-Dipeptidase A (métabolisme)</term>
<term>Pneumopathie virale (génétique)</term>
<term>Pneumopathie virale (immunologie)</term>
<term>Pneumopathie virale (prévention et contrôle)</term>
<term>Pneumopathie virale (traitement médicamenteux)</term>
<term>Récepteurs viraux (génétique)</term>
<term>Récepteurs viraux (métabolisme)</term>
<term>Souris (MeSH)</term>
<term>Souris de lignée BALB C (MeSH)</term>
<term>Souris transgéniques (MeSH)</term>
<term>Vaccins antiviraux (immunologie)</term>
<term>Vieillissement (immunologie)</term>
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<term>Interferon-alpha</term>
<term>Interferons</term>
<term>Interleukins</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en">
<term>Forkhead Transcription Factors</term>
<term>Peptidyl-Dipeptidase A</term>
<term>Receptors, Virus</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en">
<term>Viral Vaccines</term>
</keywords>
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<term>Peptidyl-Dipeptidase A</term>
<term>Receptors, Virus</term>
</keywords>
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<term>Interferon-alpha</term>
<term>Interferons</term>
<term>Interleukins</term>
</keywords>
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<term>Interferon-alpha</term>
<term>Interferons</term>
<term>Interleukins</term>
</keywords>
<keywords scheme="MESH" type="chemical" xml:lang="en">
<term>Angiotensin-Converting Enzyme 2</term>
<term>COVID-19 Vaccines</term>
</keywords>
<keywords scheme="MESH" qualifier="administration et posologie" xml:lang="fr">
<term>Interféron alpha</term>
<term>Interférons</term>
<term>Interleukines</term>
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<term>Betacoronavirus</term>
</keywords>
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<term>Coronavirus Infections</term>
<term>Pneumonia, Viral</term>
</keywords>
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<term>Betacoronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en">
<term>Coronavirus Infections</term>
<term>Pneumonia, Viral</term>
</keywords>
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<term>Facteurs de transcription Forkhead</term>
<term>Infections à coronavirus</term>
<term>Peptidyl-Dipeptidase A</term>
<term>Pneumopathie virale</term>
<term>Récepteurs viraux</term>
</keywords>
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<term>Betacoronavirus</term>
<term>Infections à coronavirus</term>
<term>Pneumopathie virale</term>
<term>Vaccins antiviraux</term>
<term>Vieillissement</term>
</keywords>
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<term>Aging</term>
<term>Betacoronavirus</term>
<term>Coronavirus Infections</term>
<term>Pneumonia, Viral</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr">
<term>Peptidyl-Dipeptidase A</term>
<term>Récepteurs viraux</term>
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<term>Betacoronavirus</term>
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<term>Betacoronavirus</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr">
<term>Interféron alpha</term>
<term>Interférons</term>
<term>Interleukines</term>
</keywords>
<keywords scheme="MESH" qualifier="prevention & control" xml:lang="en">
<term>Coronavirus Infections</term>
<term>Pandemics</term>
<term>Pneumonia, Viral</term>
</keywords>
<keywords scheme="MESH" qualifier="prévention et contrôle" xml:lang="fr">
<term>Infections à coronavirus</term>
<term>Pandémies</term>
<term>Pneumopathie virale</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr">
<term>Infections à coronavirus</term>
<term>Pneumopathie virale</term>
</keywords>
<keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr">
<term>Interféron alpha</term>
<term>Interférons</term>
<term>Interleukines</term>
</keywords>
<keywords scheme="MESH" xml:lang="en">
<term>Animals</term>
<term>COVID-19</term>
<term>Disease Models, Animal</term>
<term>Female</term>
<term>Humans</term>
<term>Male</term>
<term>Mice</term>
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<term>Mice, Transgenic</term>
<term>Models, Molecular</term>
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<term>Femelle</term>
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<term>Modèles moléculaires</term>
<term>Mâle</term>
<term>Souris</term>
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<front>
<div type="abstract" xml:lang="en">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
<sup>1</sup>
. Small animal models that recapitulate SARS-CoV-2 disease are needed urgently for rapid evaluation of medical countermeasures
<sup>2,3</sup>
. 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)
<sup>4</sup>
. Here we used reverse genetics
<sup>5</sup>
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
<sup>6</sup>
.</div>
</front>
</TEI>
<pubmed>
<MedlineCitation Status="MEDLINE" Owner="NLM">
<PMID Version="1">32854108</PMID>
<DateCompleted>
<Year>2020</Year>
<Month>10</Month>
<Day>29</Day>
</DateCompleted>
<DateRevised>
<Year>2021</Year>
<Month>01</Month>
<Day>21</Day>
</DateRevised>
<Article PubModel="Print-Electronic">
<Journal>
<ISSN IssnType="Electronic">1476-4687</ISSN>
<JournalIssue CitedMedium="Internet">
<Volume>586</Volume>
<Issue>7830</Issue>
<PubDate>
<Year>2020</Year>
<Month>10</Month>
</PubDate>
</JournalIssue>
<Title>Nature</Title>
<ISOAbbreviation>Nature</ISOAbbreviation>
</Journal>
<ArticleTitle>A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures.</ArticleTitle>
<Pagination>
<MedlinePgn>560-566</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1038/s41586-020-2708-8</ELocationID>
<Abstract>
<AbstractText>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
<sup>1</sup>
. Small animal models that recapitulate SARS-CoV-2 disease are needed urgently for rapid evaluation of medical countermeasures
<sup>2,3</sup>
. 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)
<sup>4</sup>
. Here we used reverse genetics
<sup>5</sup>
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
<sup>6</sup>
.</AbstractText>
</Abstract>
<AuthorList CompleteYN="Y">
<Author ValidYN="Y" EqualContrib="Y">
<LastName>Dinnon</LastName>
<ForeName>Kenneth H</ForeName>
<Initials>KH</Initials>
<Suffix>3rd</Suffix>
<Identifier Source="ORCID">http://orcid.org/0000-0002-8942-1551</Identifier>
<AffiliationInfo>
<Affiliation>Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y" EqualContrib="Y">
<LastName>Leist</LastName>
<ForeName>Sarah R</ForeName>
<Initials>SR</Initials>
<AffiliationInfo>
<Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Schäfer</LastName>
<ForeName>Alexandra</ForeName>
<Initials>A</Initials>
<AffiliationInfo>
<Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Edwards</LastName>
<ForeName>Caitlin E</ForeName>
<Initials>CE</Initials>
<Identifier Source="ORCID">http://orcid.org/0000-0003-4228-2192</Identifier>
<AffiliationInfo>
<Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Martinez</LastName>
<ForeName>David R</ForeName>
<Initials>DR</Initials>
<AffiliationInfo>
<Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Montgomery</LastName>
<ForeName>Stephanie A</ForeName>
<Initials>SA</Initials>
<Identifier Source="ORCID">http://orcid.org/0000-0001-8012-5302</Identifier>
<AffiliationInfo>
<Affiliation>Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>West</LastName>
<ForeName>Ande</ForeName>
<Initials>A</Initials>
<AffiliationInfo>
<Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Yount</LastName>
<ForeName>Boyd L</ForeName>
<Initials>BL</Initials>
<Suffix>Jr</Suffix>
<AffiliationInfo>
<Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y">
<LastName>Hou</LastName>
<ForeName>Yixuan J</ForeName>
<Initials>YJ</Initials>
<Identifier Source="ORCID">http://orcid.org/0000-0002-8323-7243</Identifier>
<AffiliationInfo>
<Affiliation>Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.</Affiliation>
</AffiliationInfo>
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