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MMRRC Mouse Models for COVID-19 Research

ACE2 Models

The ACE2 gene (NCBI:59272) encodes the metallopeptidase angiotensin I-converting enzyme 2, the docking site for the SARS-CoV virus, which was responsible for the SARS pandemic in 2003 (PMID:14647384). More recent work shows that ACE2 also acts as a receptor for SARS-CoV-2, the culprit in the ongoing COVID-19 pandemic (PMID:32125455). Because SARS-CoV-2 appears to be optimized for binding the human receptor (PMID:32094589), transgenic mice expressing human ACE2 are excellent models for SARS-CoV-2 infection studies.

Strain Name Mutation Availability RRID/Order
B6J.Cg-Tg(FOXJ1-ACE2)1Rba/Mmnc Transgenic mice overexpressing human ACE2 under the control of the human forkhead box J1 (FOXJ1 – NCBI:2302) promoter, which is active in lung ciliated epithelial cells. RT-PCR analysis revealed expression in the lungs but also in other tissues (PCR - brain, liver, kidney, GI – PMID:26976607). The model also expresses mouse Ace2. Utility as a SARS-CoV-2 infection model has been confirmed (PMID:32516571). Cryo-recovery MMRRC_066719-UNC
B6J.B6N(Cg)-Ace2tm1c(KOMP)Wtsi/LazarMmucd Conditional-ready model in which exon 4 of the murine Ace2 gene is floxed. The neomycin cassette has been removed (KOMP allele details). Mating with a Cre deleter strain will excise exon 4 in tissues where the recombinase is active. This model does not express human ACE2. Live Mice MMRRC_066973-UCD
B6;129S5-Ace2tm1Lex/Mmucd Exon 1 of murine Ace2 was deleted via homologous recombination, and the genetic alteration was confirmed via Southern (PMID:20562862). This model does not express human ACE2. Embryo/Sperm MMRRC_031665-UCD
C57BL/6N-Ace2em1(ACE2)Mbp/Mmucd Human DNA for ACE2 (ENSG00000130234.13) consisting of 5'UTR, CDS (exons 2-19) fused to mouse 3'UTR replaced the DNA region in mouse ACE2 gene stretching from the 5'UTR to the starting ATG in exon 2. The approach minimizes potential downstream splicing or RNP re-cleavage. CRISPR RNP was used to assist with homologous recombination using dsDNA repair in ES cells. The expression of the human CDS is controlled by the mouse regulatory systems (including 3’UTR) as the expression pattern is similar between species and especially high in the lungs. These humanized knockin ACE2 (hACE2) mice express ACE2 at a level and pattern similar to ACE2 expression in wildtype mice. In contrast, mouse ACE2 expression is 30-40 fold lower in the ACE2 mouse in which the mouse allele was interrupted by the human coding sequence. Please see the strain detail page for complete details. Please see the strain detail page for complete details. Live Mice/Sperm MMRRC_068346-UCD

ADAM17 Models

The ADAM17 gene (NCBI:6868) encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. It regulates the release of the ACE2 extracellular N-terminal domain containing the active site (“ectodomain shedding” – PMID:15983030). Since ACE2 must be membrane-associated to act as a SARS-CoV receptor (PMID: 19411314), ADAM17 has impact on SARS-CoV infection. Reviews of these findings discuss a potential role for ADAM17 in COVID-19 (PMID:32291449).

Strain Name Mutation Availability RRID/Order
C57BL/6J-Adam17m1Btlr/Mmjax A T-to-A transversion at nucleotide position 1027 predicts a phenylalanine-to-isoleucine substitution at amino acid position 343 of the protein (F343I). Sperm/Cryo-recovery MMRRC_034295-JAX

BSG Models

BSG (NCBI:682) encodes the basigin (Ok blood group) protein, which is an invasion pathway candidate for SARS-CoV-2 (PMID:32361911).

Strain Name Mutation Availability RRID/Order
B6J.Cg-Bsgtm1.1Riki Lyz2tm1(cre)Ifo/Mmmh Tissue-specific knockout of Bsg exons 2-8 through cross of the floxed strain (unpublished commercial production) with B6.129P2-Lyz2tm1(cre)Ifo/J (RRID:IMSR_JAX:004781). A roxed neomycin-cassette in the Bsg allele was self-deleted in vitro. Cryo-recovery MMRRC_046273-MU

DPP4 Models

DPP4 (NCBI:1803) encodes dipeptidyl peptidase 4, the receptor for MERS-CoV viruses (PMID:23486063). Humanized Dpp4 mice harboring genetic alterations that enhance the animals’ coronavirus infection susceptibility (e.g., A288L and T330R – PMID:27892925 PMID:24574399) serve as a model for Middle East Respiratory Syndrome and may provide insight into COVID-19 etiology.

Strain Name Mutation Availability RRID/Order
C57BL/6N-Dpp4em1(DPP4)Mbp/Mmucd In this model, exons 2-26 of human DPP4 (ENSG00000197635) have been inserted in-frame into exon 2 of the mouse Dpp4 gene. The insert contains four silent mutations in the coding sequence to prevent CRISPR RNP re-cleavage (see HGVS nomenclature below); it uses the human 3' UTR to terminate transcription and to prevent potential downstream splicing or RNP re-cleavage. Expression is controlled by the mouse regulatory systems and is predicted to terminate with the transgene’s STOP codon without expression of the endogenous sequence. The expression pattern is similar between mice and humans, and it is especially high in the lungs. (Note: Exon 2 is mouse/human chimeric, replacing the murine sequence from the 10th amino acid on (where 1 = Met/ATG). However, the predicted amino acid sequence of the transgene product is 100% identical to the human protein since the first 13 residues match between mice and man. This chimeric approach was chosen to promote intron 1 stability.) Live Mice/Sperm MMRRC_068166-UCD

SLC6A20 Models

SLC6A20 (NCBI:54716) encodes the solute carrier family 6, member 20, which interacts with the COVID-19 receptor ACE2. A European GWAS found, first, susceptibility to and protection from COVID-19 respiratory failure for blood types A and 0, respectively, and second, a possible role for SLC6A20 in the COVID-19 genetic puzzle (DOI: https://doi.org/10.1101/2020.05.31.20114991). Mouse models addressing this connection must consider that human SLC6A20 has two murine orthologs, Slc6a20a (MGI:2143217) and Slc6a20b (MGI:1336891).

Strain Name Mutation Availability RRID/Order
C57BL/6N-Slc6a20bem1(IMPC)J/Mmucd The gene holds a 183-bp deletion ablating all of exon 3 as well as flanking intronic sequences. It is predicted to produce 10 non-sense amino acids C-terminal to codon 131 followed by early truncation. Cryo-recovery MMRRC_049751-UCD

STAT1 Models

The STAT1 gene (NCBI:6772) encodes the 'signal transducer and activator of transcription 1' protein, which co-initiates the interferon response. It has been implicated in SARS-CoV pathogenesis (PMID:20386712), and Stat1 knockout leads to symptom worsening and disease prolongation, suggesting a protective role for Stat1, helping SARS-CoV clearance (PMID:15452265). Whether or not STAT1 plays a role in COVID-19 etiology is, so far, unclear.

Strain Name Mutation Availability RRID/Order
C57BL/6JSfdAnu-Stat1m1Anu/AnuApbMmucd The strain was produced by the ENU mutagenesis program at the Australian Phenomics Facility at The Australian National University. It harbors a T-to-A change at nucleotide 1633 (NM_001205313.1:c1633T>A) predicting an amino substitution from tryptophan to arginine at codon 545 (p.Trp545Arg or W545R).

Caution – this model was generated with non-targeted, chemical mutagenesis. Alterations in other genes have not been reviewed. 		Cryo-recovery MMRRC_041265-UCD
B6;129S-Stat1tm1Mam/Mmjax Conditional-ready model in which the first two untranslated exons and the first translated exon are enveloped by loxP sites. Mating with a Cre deleter strain will excise the floxed exons in tissues where the recombinase is expressed. Cryo-recovery/Sperm MMRRC_032054-JAX
C57BL/6-Stat1fae/Mmucd The strain was produced by the ENU mutagenesis program at the Australian Phenomics Facility at The Australian National University. This strain harbors a T-to-A transversion at nucleotide 1979 predicting a methionine-to-lysine exchange at codon 660 (p.Met660Lys or M660K).

Caution – this model was generated with non-targeted, chemical mutagenesis. Alterations in other genes have not been reviewed. 		Cryo-recovery MMRRC_031690-UCD

TICAM2 Models

In mice, genetic ablation of the toll-like receptor adaptor molecule 2 (Ticam2 – MGI:3040056) elevates SARS-CoV infection susceptibility and produces weight loss as well as pulmonary hemorrhage (PMID:28592648). It is uncertain if the human ortholog (TICAM2- NCBI:353376) contributes to the SARS-CoV-2 disease response.

Strain Name Mutation Availability RRID/Order
C57BL6/J-Ticam2tm1Btlr/Mmucd Exon 3, which encompasses the entire coding region of the gene, was replaced with a neo cassette. No transcript was detected in homozygotes (PMID:17292937). Cryo-recovery/Sperm/Embryo MMRRC_030018-UCD

TMPRSS2 Models

The TMPRSS2 gene (NCBI:7113) encodes transmembrane serine protease 2. Along with ACE2, this protease aids in SARS-CoV-2 cell entry (PMID:32142651).

Strain Name Mutation Availability RRID/Order
B6N.129S5-Tmprss2tm1Lex/Mmucd The first and second coding exon of murine Tmprss2 (NCBI:NM_015775.2) were targeted by homologous recombination (PMID:20562862) and the disruption was confirmed via Southern. The model is on a C57BL/6N-congenic background. Sperm MMRRC_032679-UCD
B6;129S5-Tmprss2tm1Lex/Mmucd Same model as above but on a mixed background combining C57BL/6 and 129S5/SvEvBrd. Sperm/Embryo MMRRC_032678-UCD
C57BL/6N-Tmprss2em1(TMPRSS2)Mbp/Mmucd Exons 3-14 of human TMPRSS2 (ENSG00000184012.14) have been inserted in-frame into exon 2 (ENSMUSE00000641779) of the mouse Tmprss2 gene. CRISPR RNP was used to assist with homologous recombination (HR) using dsDNA repair template in ES cells. The mouse exon 2 splice acceptor and the guide protospacer (nt 1-17) were removed from the HR template to prevent potential downstream splicing or RNP re-cleavage. The expression of the human CDS is controlled by the mouse regulatory systems (including 3’UTR), and predicted to terminate with the transgene’s STOP codon without expression of the endogenous sequence. The expression pattern for Tmprss2/TMPRSS2 is similar between mice and humans, and it is especially high in the lungs. Live Mice/Sperm MMRRC_068347-UCD

TRAF6 Models

TRAF6 (NCBI:7189) encodes TNF receptor-associated factor 6. SARS-CoV appears to evade the innate immune response by targeting mitochondrial Traf6 and suppressing interferon action (PMID:25135833).

Strain Name Mutation Availability RRID/Order
B6J.129P2-Traf6tm1Mak/Mmjax Homologous recombination replaced the exon containing the ATG translation initiation codon with a PGK-neomycin cassette in the opposite orientation (PMID:10215628). The exon encodes the first 100 amino acids of Traf6, representing a portion of the amino-terminal zinc RING-finger domain. Live Mice/Sperm MMRRC_044044-JAX
TRIM55 Models

Genome wide susceptibility mapping using Collaborative Cross mice revealed that Trim55 (MGI:3036269), the gene encoding the 'tripartite motif-containing 55' protein, contributes to lung pathology in SARS-CoV-infected mice (PMID:26452100). It is unclear if the human ortholog (TRIM55 - NCBI:84675) contributes to SARS-CoV associated pulmonary complications.

Strain Name Mutation Availability RRID/Order
C57BL/6N-Trim55tm2a(EUCOMM)Hmgu/BayMmucd Conditional-ready model where exon 2 of the Trim55 gene has been floxed. Mating with a Cre deleter strain will excise the exon in tissues where the recombinase is expressed. Cryo-recovery/Sperm MMRRC_041252-UCD

Additional COVID-19 Related Genes

The following genes have demonstrated or plausible relevance in COVID-19 pathogenesis, but the MMRRC currently holds no mouse models or embryonic stem cells expressing the human gene or targeting the murine ortholog. Interested in developing a model?


Contact the MMRRC regarding fast-track production of a model targeting these genes.

FURIN Models

FURIN (NCBI:5045) encodes the paired basic amino acid cleaving enzyme, which targets a polybasic cleavage site found at the junction of the two SARS-CoV-2 spike subunits (PMID:32155444) This affects virus transmissibility & pathogenesis (PMID:32362314).


MUC4 Models

MUC4 (NCBI:4585) encodes the mucin 4 cell surface-associated protein, a candidate for controlling the SARS-CoV titer. This emerged from a genome-wide study seeking to identify SARS-CoV susceptibility loci using genetically diverse animals from incipient lines of the Collaborative Cross mouse panel (PMID:26452100). Subsequent sequence analyses and RNA expression studies within the QTL point at Muc4 (bioRxiv 2020.02.19.957118 – not peer-reviewed or PubMed-indexed, yet).