Mouse Genome Informatics Coronavirus Information Center
Mouse Models for Coronavirus Research
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 5/4/2021
Coronavirus disease (COVID-19) is an infectious disease caused by a novel member of the coronavirus family of viruses. As of early May 2021, more than 153.7 million cases of COVID-19 have been documented in 192 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 are many efforts underway to develop treatments and vaccines for COVID-194.
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.
A 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.
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.
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.
BALB/c mice intranasally inoculated with a replication-defective adenovirus encoding the hACE2 receptor are productively infected with SARS-CoV-2, exhibiting high viral titers in the lung, lung pathology, and weight loss. Passive transfer of a neutralizing monoclonal antibody reduces viral burden in the lung and mitigates inflammation and weight loss.
A knock-in mouse line that expresses the human gene for angiotensin-converting enzyme 2 (ACE2), under the control of the endogenous mouse Ace2 promoter. Both young and aged mutant mice sustain high viral loads in lung, trachea, and brain upon intranasal infection. Aged SARS-CoV-2 infected mice show interstitial pneumonia and elevated cytokines. Intragastric inoculation of SARS-CoV-2 also caused productive infection and lead to pulmonary pathological changes.
Intranasal infection of C57BL/6J mice with SARS-CoV MA15 (the mouse-adapted SARS-CoV) results in high-titer virus replication within the lung, induction of inflammatory cytokines and chemokines, and immune cell infiltration within the lung. Mice deficient in C3 (C3-/-) are protected from SARS-CoV MA15-induced weight loss and show reduced pathology, improved respiratory function and lower levels of inflammatory cytokines/chemokines in the lung and periphery than C57BL/6J controls.
A 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).
A 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.
A 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).
A transgenic mouse line 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.
Replication 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.
Infected 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.
Replication 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.
Evaluated 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.
DPP4 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.
The 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-CoV
Dpp4tm1.1(DPP4)Pbmj
on a mixed inbred strain background including C57BL/6 and C57BL/6NTac
Mice 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.
Genome 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.
The 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-CoV
Dpp4tm1(DPP4)Vlcg
on a mixed inbred strain background including 129S6/SvEvTac and C57BL/6NTac
This 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.
ACE2 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).
Grunewald et al. (2020) demonstrated that Ahr is activated in cells infected with mouse hepatitis virus (MHV) and contributes to the upregulation of downstream effector TCDD-inducible poly(ADP-ribose) polymerase (Tiparp) during infection. Knockdown of Tiparp reduced viral replication and increased interferon expression, suggesting it functions in a proviral manner during MHV infection.
Study by Do Carmo et al. (2008) demonstrated that Apod transcripts and protein are upregulated during acute encephalitis induced in mice infected with a human coronavirus ( HCoV-OC43). Apod regulates inflammation and has a protective role against the coronavirus, presumably through the phospholipase A2 signaling pathway.
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.
Human CD209 (aka CLEC4M, CD209L, L-SIGN) binds purified soluble SARS-CoV spike (S) glycoproteins expressed in various cell cultures. The data show that CD209 can serve to facilitate the entry of SARS-CoV into cells.
DPP4 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.
Zalinger et al. (2015) demonstrated that mice deficient in Ifih1 (aka, Mda5) experienced more severe disease following infection of the liver with mouse hepatitis virus (MHV). Ifih1 normally participates in the activation of type 1 interferon in response to the presence of viral RNA. Fisher et al. (2020) propose that the loss of IFIH1 in pangolins may have contributed to the role these mammals play as reservoirs of zoonotic viruses.
Study by Ireland et al. (2008) demonstrates the critical role of type I interferon in controlling murine hepatitis virus (MHV) dissemination within the central nervous system.
Trandem et al. (2011) showed that IL10 produced by CD8+ T cells diminished severity of encephalitis in mice with coronavirus-induced acute encephalitis. Han et al. (2020) reported that high levels of IL6 and IL10 are associated with critical COVID-19 disease in patients.
Work by Plante et al. in incipient Collaborative Cross mouse lines suggests that Muc4 expression plays a protective role in female mice not conserved in male mice following SARS-CoV infection. Treatments that modulate or enhance Muc4 activity may provide an avenue for treatment and improved outcomes. It is not known if the findings in mice hold true for humans.
Infection with a mouse-adapted SARS-CoV virus (rMA15) is lethal in BALB/c mice but causes a non-lethal infection in C57BL/6 mice. Mice deficient in Myd88 are more susceptible to rMA15. Data suggest that Myd88-mediated innate immune signaling and inflammatory cell recruitment to the lung are required for protection from lethal rMA15 infection.
SARS-CoV2 binds NRP1 in human cell culture enhancing viral infection. Potential role in neurological targets based on transport studies of viral sized particles in mice (in Cantuti-Castelvetri paper).
STAT1 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).
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.
Grunewald et al. (2020) demonstrated that Ahr is activated in cells infected with mouse hepatitis virus (MHV) and contributes to the upregulation of downstream effector TCDD-inducible poly(ADP-ribose) polymerase (Tiparp) during infection. Knockdown of Tiparp reduced viral replication and increased interferon expression, suggesting it functions in a proviral manner during MHV infection.
Imai et al. (2008) observed that mice exposed to SARS produce oxidized phospholipid in their lungs and that Toll-like receptor 4 (Tlr4) deficient mice display natural resistance to lung injury. Direct relevance to SARS pathology not certain.
TMPRSS2 encodes the protease that "primes" the S-protein, necessary for SARS-CoV to bind to 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.
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.
Tan et al. (2012) demonstrated that small interfering RNA (siRNA) against human ZCRB1 (aka, MADP1) led to defective viral RNA synthesis in SARS-CoV in knockdown cells, indicating the importance of the protein in coronaviral RNA synthesis. No studies have been published using mouse models.
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.
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.
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.
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.
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
ScienceDaily "HLH research points to treatment for COVID-19 cytokine storms" (May 28, 2020)
News-Medical.Net "Transgenic mouse model of HLH may play key role in saving lives during COVID-19" (May 28, 2020)
Times Now "Coronavirus: Mouse model mimics COVID-19 infection in humans, may help test drugs" (May 28, 2020)
Taconic "An overview of mouse models for COVID-19" (May 30, 2020)
SciTechDaily "New research points to treatment for COVID-19 cytokine storms, solution to global pandemic" (May 31, 2020)
RegMedNet "COVID-19 treatment breakthrough using fibroblast cell therapy in mice" (June 1, 2020)
HospiMedica "Transgenic mouse that models immune disease's cytokine storms could point to treatment solution for COVID-19" (June 5, 2020)
Nordic Life Science News "A vaccine against COVID-19, developed by researchers from the Univ. of Copenhagen, has been tested in mice and shows promising results" (June 10, 2020)
Arizona Republic "Mice can't catch COVID-19, so a UA lab is making new kind of mouse" (June 10, 2020)
MedicalXpress "COVID-19 mouse model will speed search for drugs, vaccines" (June 10, 2020)
The Economist "An animal model of COVID-19 is now available" (June 11, 2020)
Study Finds "COVID-19 mouse model may hold key to new treatments, understanding risk factors" (June 13, 2020)
MedicalXpress "Off-the-shelf tool for making mouse models of COVID-19" (June 16, 2020)
Drug Target Review "Method to convert any mouse into COVID-19 model made available to researchers" (June 22, 2020)
The Daily Iowan "University of Iowa researchers develop mice model to study COVID-19 symptoms" (June 28, 2020)
The New Yorker "Can designer mice save us from COVID-19?" (August 10, 2020)
Science Daily "Study finds COVID-19 attack on brain, not lungs, triggers severe disease in mice" (January 19, 2021)
EurekAlert "NSAIDs might exacerbate or suppress COVID-19 depending on timing, mouse study suggests" (January 22, 2021)
Yahoo News "Researchers found far higher levels of coronavirus in the brains of mice than the lungs - a possible explanation for neurological symptoms" (January 28, 2021)
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