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Mouse Genome Informatics Coronavirus Information Center

Mouse Models for Coronavirus Research

COVID-19alert mouse
About this resource: MGI is a knowledgebase of mouse models of human disease. To aid the research community in addressing the COVID-19 pandemic, we have collected expertly curated information on publications, mouse models and both human and mouse genes relevant to coronavirus research. This special collection will be updated regularly. – Updated 6/2/2020
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Table of Contents

The COVID-19 Pandemic of 2020

Coronavirus disease (COVID-19) is an infectious disease caused by a novel member of the coronavirus family of viruses. As of early June 2020, more than 6.3 million cases of COVID-19 have been documented in over 180 countries/regions worldwide1,2.

The virus that causes COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was likely transmitted to humans from an animal reservoir. The exact nature of this transmission is still under investigation3.

There is no vaccine or proven treatment for COVID-19 although there are many efforts underway to develop them4.

 
SARS-CoV-2
Figure 1. This transmission electron microscope image shows virus particles of SARS-CoV-2 emerging from the surface of cells from a COVID-19 patient cultured in the lab. The spikes on the periphery of the virus particles give coronaviruses their name (Latin derivation; corona=crown). Photo Credit: NIAID-RML
 

Coronavirus Research in the Laboratory Mouse

The laboratory mouse is an important preclinical model for studying coronavirus biology and treatment approaches. The tables below summarize information about strains and genes relevant to the study of coronavirus in mouse. This information was obtained from the Mouse Genome Informatics (MGI) knowledgebase hosted at The Jackson Laboratory and from the International Mouse Strain Resource (IMSR).

MGI’s biocuration scientists are monitoring the peer-reviewed scientific literature for new reports and will update the MGI database weekly. You can help this effort by notifying MGI’s Help Desk about references in the peer-reviewed literature about the use of the mouse in coronavirus research that are missing from our database.

See all curated scientific publications that report on mouse models for coronavirus research in MGI

TABLE 1: MOUSE STRAINS USED TO STUDY SARS AND MERS CORONAVIRUSES
Coronavirus InvestigatedMouse Strain Name  Mouse Strain AvailabilityStudy Type  Reference(s)  Summary
SARS-CoV-2ICR-Tg(Ace2-ACE2)1Cqin/J on an ICR backgroundNo repository listing COVID-19

Coronavirus infection
Bao et al. 2020A transgenic mouse strain that expresses the human gene for angiotensin-converting enzyme 2 (hACE2) (the cellular receptor of SARS-CoV and SARS-CoV-2), driven by the mouse Ace2 promoter. Transgenic mice infected with SARS-CoV-2 exhibit weight loss and virus replication in lung; these mice develop interstitial pneumonia similar to human COVID-19 patients.
SARS-CoVB6.Cg-Tg(K18-ACE2)2Prlmn/JJAX:034860*

*This model is being expanded as a possible model for the study of SARS-CoV-2

Coronavirus infection

Severe acute respiratory syndrome
McCray et al. 2007A transgenic mouse strain that expresses the human version of the SARS-CoV receptor (ACE2; angiotensin-converting enzyme 2) developed to study the pathobiology of SARS-CoV and to aid in development of antiviral therapeutics. These mice develop severe acute respiratory syndrome (SARS).
SARS-CoVBALB/c

Rag1tm1Mom
BALB/c from Envigo. The exact strain is not specified.

Rag1tm1Mom from JAX. The exact stock is not specified.
Coronavirus infection Menachery et al. 2020The investigators evaluated the use of 2’O MTase mutants as a live-attenuated vaccine platform to rapidly respond to current and future CoV strains.
SARS-CoVB6.Cg-Tg(FOXJ1-ACE2)1Rba/Mmnc on a mixed C3H and C57BL/6 genetic backgroundRelated Strain: MMRRC:066719Coronavirus infection

Severe acute respiratory syndrome
Menachery et al. 2016A transgenic mouse strain that expresses the human version of the SARS-CoV receptor (ACE2; angiotensin-converting enzyme 2) under the control of the ciliated epithelial cell-specific promoter elements of the human FOXJ1 promoter. This mouse is particularly susceptible to severe acute respiratory distress syndrome corona virus (SARS-CoV).
SARS-CoVTg(CAG-ACE2)AC70Ctkt and
Tg(CAG-ACE2)AC63Ctkt on mixed genetic backgrounds
No repository listingCoronavirus infection

Severe acute respiratory syndrome
Yoshikawa et al. 2009 and Tseng et al. 2007A transgenic mouse strain that expresses human angiotensin-converting enzyme 2, under the regulation of a global promoter. These mice are highly susceptible to SARS-CoV infection and show weight loss and other clinical manifestations before reaching 100% mortality within 8 days after intranasal infection.
SARS-CoVICR-Tg(Ace2-ACE2)1Cqin/J on an ICR backgroundNo repository listingCoronavirus infection

Severe acute respiratory syndrome
Yang et al. 2007A transgenic mouse strain that expresses the human gene for angiotensin-converting enzyme 2 (hACE2) (the cellular receptor of SARS-CoV), driven by the mouse Ace2 promoter. Mice infected with SARS-CoV show severe pathologic changes that resemble human SARS infection.
SARS-CoVBALB/cBALB/c mice distributed from several respositories. The exact strain used in the study is not clear.Coronavirus infection Roberts et al. 2005Replication of SARS-CoV was observed in lung and intestinal tissue in 12- 14 month old BALB/c mice inoculated intranasally. These animals displayed clinical signs of illness and pneumonia similar to humans.
SARS-CoVC57BL/6JJAX:000664Coronavirus infection Glass et al. 2004Infected mice had a relative failure to thrive, gaining weight significantly more slowly than uninfected mice, but recover. C57BL/6J mice support transient nonfatal systemic infection with SARS-CoV in the lung and brain.
SARS-CoVBALB/cBALB/c mice distributed from several respositories. The exact strain used in the study is not clear.Coronavirus infection Wentworth et al. 2004Replication of SARS-CoV was observed in lung and intestinal tissue in 4 week old BALB/c mice inoculated intranasally and orally. Infected mice did not display clinical signs of illness.
MERS-CoVDpp4tm1.1(DPP4)Pbmj on a C57BL/6NTac backgroundNo repository listingCoronavirus infection

Middle East respiratory syndrome
Li et al. 2020Evaluated a parainfluenza virus 5 (PIV5)-based vaccine expressing the MERS-CoV envelope spike protein (PIV5/MERS-S) in a human DPP4 knockin C57BL/6 congenic mouse model (hDPP4KI). Following a single-dose intranasal immunization, PIV5-MERS-S induced neutralizing antibody and robust T cell responses in hDPP4KI mice.
MERS-CoVTg(DPP4)2Nnag
on a C57BL/6J background
No repository listingCoronavirus infection

Middle East respiratory syndrome
Iwata-Yoshikawa et al. 2019 and Iwata-Yoshikawa et al. 2019DPP4 encodes the viral receptor of Middle East respiratory-coronavirus (MERS-CoV). Transgenic (Tg) mice on a C57BL/6NCr background express human DPP4 under control of the endogenous promoter. Intranasal inoculation of young and adult Tg mice with MERS-CoV led to infection of the lower respiratory tract and pathological evidence of acute multifocal interstitial pneumonia within 7 days, with symptoms more severe in older mice.
MERS-CoVGt(ROSA)26Sorem1(DPP4)Yowa
on a C57BL/6 background
No repository listingCoronavirus infection

Middle East respiratory syndrome
Fan et al. 2018The human DPP4 cDNA, the viral receptor of Middle East respiratory-coronavirus (MERS-CoV) was inserted into the Gt(ROSA)26Sor locus using CRISPR/Cas9. Transgenic mice are susceptible to infection with the Middle East respiratory syndrome coronavirus (MERS-CoV) strain hCoV-EMC.
MERS-CoVDpp4tm1.1(DPP4)Pbmj
on a mixed inbred strain background including C57BL/6 and C57BL/6NTac
No repository listingCoronavirus infection

Middle East respiratory syndrome
Li et al. 2017Mice with a humanized Dpp4 gene were inoculated with MERS-CoV. Exons 10-12 (from codon I264 in exon 10 to codon V340 in exon 12) of the mouse were replaced with the corresponding human exons of 10-12 which comprise the critical Middle East respiratory syndrome coronavirus (MERS-CoV) receptor. After 30 passages, a mouse adapted virus (MERSMA) emerged.
MERS-CoV
MERS-15
C57BL/6J-Dpp4em1RbaNo repository listingCoronavirus infection

Middle East respiratory syndrome
Cockrell et al. 2016Genome editing was used to humanize the mouse Dpp4 (dipeptidyl peptidase 4 receptor) gene so match the human gene and make mice susceptible to MERS-CoV infection and replication. A mouse adapted MERS-CoV strain (MERS-15) induced severe acute respiratory like disease in infected animals.
MERS-CoVTg(KRT18-DPP4)3Pbmj
on a mixed C57BL/6J and SJL/J genetic background
No repository listingCoronavirus infection

Middle East respiratory syndrome
Li et al. 2016Transgenic mice express human DPP4 (hDPP4) under the control of the cytokeratin 18 promoter that renders susceptiblity to infection with MERS-CoV.
MERS-CoVTg(CAG-DPP4)52Ctkt
on a mixed inbred strain including C3H/HeJ and C57BL/6J
No repository listingCoronavirus infection

Middle East respiratory syndrome
Agrawal et al. 2015The human DPP4 cDNA, the viral receptor of Middle East respiratory-coronavirus (MERS-CoV), generated from the mRNA of human phytohemagglutinin-activated T cells, is expressed under the control of a ubiquitous promoter. Mice are susceptible to infection with the EMC-2012 strain of the Middle East respiratory-coronavirus (MERS-CoV) and develop an acute wasting syndrome, with progressive weight loss starting at 2 days post infection.
MERS-CoVDpp4tm1(DPP4)Vlcg
on a mixed inbred strain background including 129S6/SvEvTac and C57BL/6NTac
129S6/SvEvTac
C57BL/6NTac
Coronavirus infection

Middle East respiratory syndrome
Pascal et al. 2015This mouse model is comprised of an 82 kb human DPP4 genomic DNA from exons 2–26, including 3′UTR which replaced the 79-kb mouse Dpp4 counterpart sequence. The model also expresses components of the human immune system (antibody-variable heavy chains and kappa light chains) and is capable of developing human antibodies against MERS-CoV.
MERS-CoVC57BL/6-Tg(CAG-DPP4)4YuzhNo repository listingCoronavirus infection

Middle East respiratory syndrome
Zhao et al. 2015A transgenic mouse model globally expressing codon-optimized human dipeptidyl peptidase 4 (hDPP4), the receptor for MERS-CoV.
TABLE 2: GENES ASSOCIATED WITH CORONAVIRUS INFECTION AND PATHOLOGY
Human GeneMouse Gene  CommentsReferences
ACE2
angiotensin I converting enzyme (peptidyl-dipeptidase A) 2
Ace2ACE2 encodes the receptor that SARS viruses use to infect a cell (Li et al., 2003, Hoffmann et al., 2020). The mouse version of the ACE2 receptor doesn’t bind SARS-CoV as efficiently as the human form. To make the mouse more useful as a model for productive SARS coronavirus infection, several groups have generated transgenic animals that express the human ACE2 gene. These transgenic mice are good models for SARS-CoV infection (the virus responsible for the 2002-2003 SARS pandemic), and may also prove effective as models for COVID-19 disease, due to the genetic similarity between SARS-CoV and SARS-CoV-2 (the virus responsible for the COVID-19 pandemic).Li et al. 2003
Hoffmann et al. 2020
APOE
apolipoprotein E
Apoe APOE e4 genotype predicts severe COVID-19 in the UK BioBank, independent of dementia, cardiovascular disease and diabetes.Kuo et al. 2020
BSG
basigin
Bsg BSG (CD147) interacts with the spike protein of SARS-CoV-2 to facilitate entry into cells. A humanized anti-CD147 antibody (Meplazumab) competitively inhibits the binding of the spike protein and BSG and prevents viral entry into cells.Wang et al. 2020
DPP4
dipeptidylpeptidase 4
Dpp4DPP4 encodes the receptor that MERS-CoV viruses use to infect a cell (Raj et al., 2013). To make the mouse a useful model, genome editing was used to introduce two amino acid changes, an alanine to leucine substitution at amino acid 288 (A288L) in exon 10 and a threonine to arginine substitution at amino acid 330 (T330R) in exon 11 (Cockrell et al, 2016). These two changes match the human sequence, making mice susceptible to Middle East respiratory syndrome coronavirus infection and replication.Rai et al. 2013
Cockrell et al. 2016
STAT1
signal transducer and activator of transcription 1
Stat1STAT1 plays a key role in development of acute lung injury associated with SARS pathology (Frieman et al., 2010). Stat1 knockout mice infected with SARS-CoV developed interstitial pneumonia but did not develop diffuse alveolar damage (Hogan et al., 2004).Frieman et al. 2010
Hogan et al. 2004
TMPRSS2
transmembrane protease, serine 2
Tmprss2TMPRSS2 encodes the protease that "primes" the S-protein, necessary for SARS-CoV to bind to the ACE2 (Matsuyama et al, 2010; Bertram et al., 2011). Using mouse models, Iwata-Yoshikawa et al. (2019), demonstrated that the loss of the Tmprss2 protein in airways reduces the severity of lung damage following infection by SARS-CoV and MERS-CoV suggesting that TMPRSS2 may be a good target for treatment of coronavirus infection.Matsuyama et al. 2010
Bertram et al. 2011
Iwata-Yoshikawa et al. 2016
 Trim55

tripartite motif-containing 55
Genetic mapping using Collaborative Cross mice revealed Trim55 as a gene contributing to lung pathology (inflammation and vascular cuffing) in SARS-CoV infected mice. It is not known if human TRIM55 also contributes to these pulmonary phenotypes following infection with SARS-CoV.Gralinsky et al. 2015
 Ticam2

toll-like receptor adaptor molecule 2
Ticam2 is an innate immune system modulatory gene. Using two strains of Collaborative Cross mice, Gralinsky et al. demonstrated that mice with a loss of Ticam2 were highly susceptible to SARS-CoV infection and demonstrated increased weight loss and pulmonary hemorrhage compared to control mice. It is not known if variation in human TICAM2 contributes to susceptibility to SARS-CoV disease response. Gralinsky et al. 2017
TABLE 3: MICE IN CORONAVIRUS RESEARCH FROM PREPRINTS
Research described in preprints is not peer reviewed. The reported findings have not been validated.
Coronavirus  Mouse Strain Name  Reported Mouse Strain SourceStudy Type  Reference  Summary
SARS-CoVMuc4tm1Unc on a C57BL/6NTac genetic backgroundScott Randell of the University of North Carolina at Chapel Hill
Rowson-Hode et al. 2018
Coronavirus infection

Severe acute respiratory syndrome
Plante et al., 2020. bioRxiv.In this study investigators followed up on a previously mapped QTL in Collaborative Cross mice to identify genes associated with low SARS-CoV viral titer.

By evaluating gene expression of genes in the previously identified QTL region in founder strains of CC mice, mucin 4 (Muc4) emerged as a candidate gene to explain differences in viral titer.

The loss of Muc4 gene function did not result in significant differences in viral load or distribution in male and female Muc4-/- mice. Female Muc4-/- mice did, however, show significant weight loss compared to mutant male mice. The investigators conclude that Muc4 does not play a role in the replication of SARS-CoV virus but does play some role in attenuating the pathology associated with viral infection in mice.
SARS-CoVNSG mice; male and female > 6 weeks old Cleveland Clinic Biological Resources UnitCoronavirus infection

Severe acute respiratory syndrome
Baratchian et al., 2020. bioRxiv.Male NSG mice, treated with the androgen receptor antagonist enzalutamide did not decrease pulmonary TMPRSS2 expression.

The study finds no evidence for androgen regulation of TMPRSS2 in the male lung and concludes that TMPRSS2 regulation does not account for sex differences in clinical outomes of COVID-19 patients. Therefore, TMPRSS2 regulation in the lung appears to fundamentally differ from a clear androgen-dependent effect in prostatic tissues. Pulmonary TMPRSS2 regulation does not appear to account for the sex bias in COVID-19 clinical outcomes.
SARS-CoV-2BALB/c Source not identifiedCoronavirus infection

Severe acute respiratory syndrome
Gao et al., 2020. bioRxiv.An inactivated virus vaccine (PiCoVacc) generated neutralizing antibodies in BALB/c mice, Wistar rats, and macaques that were specific to SARS-CoV-2. The neutralizing antibodies worked against 10 SARS-CoV-2 strains. Antibody-dependent enhancement (ADE) of infection was not observed but cannot be ruled out.
SARS-CoV-2Mouse strain not specified Source not identifiedCoronavirus infection

Severe acute respiratory syndrome
Zeng et al., 2020. bioRxiv.De novo designed untranslated regions (UTRs) of mRNAs (NASAR mRNAs) delivered via lipid-derived nanoparticles were shown to significantly increase expression of potential SARS-CoV-2 antigens both in vitro and in vivo. NASAR mRNAs show promise for further evaluation as vaccines against SARS-CoV-2.
SARS-CoV-2BALB/cAnNHsdEnvigoCoronavirus infection

Severe acute respiratory syndrome
Dinnon III et al., 2020. bioRxiv.The SARS-CoV-2 receptor binding domain of SARS-CoV-2 was altered to create a recombinant virus (SARS-CoV-2 MA) that is capable of using the mouse Ace2 receptor for infection. The mouse adapted virus replicated in 10 week and 1 year old BALB/c mice.

Similar to observations in humans, pulmonary disease was more severe in older mice compared to young mice.

10 week old BALB/c mice vaccinated with an Venezuelan equine encephalitis virus replicon particle (VRP) system against the SARS-CoV-2 spike protein effectively neutralized the virus.

Treatment of SARS-CoV-2 MA infected mice with pegylated interferon (IFN)lambda 1a diminished the replication of the virus in mice.
SARS-CoV-2BALB/c Source not identified
(See also Roberts et al. 2007)
Coronavirus infection

Severe acute respiratory syndrome
Weston et al., 2020. bioRxiv. In this study, investigators present data showing that 17 out of 20 FDA approved drugs that previously demonstrated antiviral activity against SARS-CoV and MERS-CoV also inhibited SARS-CoV-2 in cell culture (Vero E6 cells) at a range of IC50 values at non-cytotoxic concentrations.

Seven compounds were demonstrated to inhibit infectious SARS-CoV-2 production in cell culture (chloroquine, hydroxychloroquine, chlorpromazine, amodiaquine dihydrochloride dihydrate, amodiaquine hydrochloride, mefloquine, imatinib).

Chloroquine and chlorpromazine were tested in vivo on 10 week old BALB/c mice using a mouse-adapted SARS-CoV virus (rMA15). Both drugs protected the mice from clinical disease but did not inhibit viral replication.
 

About SARS-CoV-2

SARS-CoV-2 is positive single strand RNA5 virus and is a member of the Coronaviridae family of viruses which are known to target the respiratory systems of mammals. There are four genera within Coronaviridae: alpha, beta, delta, and gamma. Only alpha and beta genera are transmissible to humans.

Although the genome of SARS-CoV-2 is similar to the zoonotic coronaviruses SARs-CoV and MERS-CoV that caused the SARs outbreak of 2003 and the MERS outbreak of 2012, the emerging evidence suggests that SARS-CoV-2 did not descend from SARS-CoV. SARS-CoV-2 causes a different range of diseases in humans and has a different transmission efficiency6.

coronavirus tree
Figure 2. The International Committee on the Taxonomy of Viruses taxonomy of Coronaviridae showing the alpha and beta coronaviruses that infect humans. Adapted from Pillaiyar et al., Drug Discovery Today, 2020

References

  1. Global cases of COVID-19 from The Johns Hopkins University
  2. WHO Coronavirus Disease (COVID-19) Dashboard
  3. The proximal origin of SARS-CoV-2 Nature Medicine 17 March 2020.
  4. COVID-19 Vaccine and Treatment Tracker from the Milken Institute
  5. Coronavirus Genome is Bad News Wrapped in a Protein (The New York Times)
  6. Taxonomy of SARS-CoV-2 Nature Microbiology 2 March 2020.
  7. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing Nature 30 April 2020.

Other Research Resources with Special Coronavirus Information

  • Gene Ontology (GO)
  • Infrafrontier
  • International Mouse Phenotyping Consortium (IMPC)
  • NextStrain visualization of the genomic epidemiology of novel coronavirus
  • PDB-101 Molecular Landscapes by David S. Goodsell
  • UniProt

Mice in the News

  • STAT News, "From ferrets to mice and marmosets, labs scramble to find right animals for coronavirus studies" (March 5, 2020)
  • Nature, "Labs rush to study coronavirus in transgenic animals – some are in short supply" (March 9, 2020)
  • Bloomberg, "A Virus Cure Depends on Rare Lab Mice, But There Aren’t Enough" (March 11, 2020)
  • STAT News, "Researchers rush to test coronavirus vaccine in people without knowing how well it works in animals" (March 11, 2020)
  • The New York Times, "These Lab Animals Will Help Fight Coronavirus" (March 14, 2020)
  • National Public Radio (NPR) "Mouse Hunt: Lab Races to Grow Mice for COVID-19 Research." (March 14, 2020)
  • Bangor Daily News, "Maine lab starts breeding mice for coronavirus vaccine" (March 18, 2020)
  • Science, "'It’s heartbreaking.' Labs are euthanizing thousands of mice in response to coronavirus pandemic" (Mar. 23, 2020)
  • The Hill, "First peer-reviewed coronavirus vaccine shows promise in mice" (April 2, 2020)
  • Scientific American, "New Coronavirus Drug Shows Promise in Animal Tests" (April 7, 2020)
  • Advanced Science News, "Mouse study shows engineered virus could block coronavirus infections" (April 8, 2020)
  • Science, "Mice, hamsters, ferrets, monkeys. Which lab animals can help defeat the new coronavirus?" (April 13, 2020)
  • Knowable Magazine, "Building a mouse squad against Covid-19" (May 14, 2020)
  • NIH News "Microneedle coronavirus vaccine triggers immune response in mice." (April 14, 2020)
  • EurekAlert "Russia creates its own humanized mice to test COVID-19 vaccines and drugs." (May 4, 2020)
  • Technology Networks "Mouse Study Explores Why COVID-19 Patients Can Lose Their Sense of Smell." (May 13, 2020)
  • Scientific American "From Hamsters to Baboons: The Animals Helping Scientists Understand the Coronavirus." (May 14, 2020)
  • WHYY PBS "The great research mouse rescue amid the pandemic." (May 15, 2020)

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