These mice express human ACE2, the receptor used by severe acute respiratory syndrome coronavirus (SARS-CoV) to gain cellular entry. The human keratin 18 promoter directs expression to epithelia, including airway epithelia where infections typically begin. Because K18-hACE2 mice are susceptible to SARS-CoV-2 and SARS-CoV viruses, they are useful for studying antiviral therapies to COVID-19 and SARS.
This strain also has the FcRn-/- targeted mutation and hFcRn (32) transgene, which may enhance the human-like protection of humanized IgG and potentially make these mice useful for developing antibody-based therapeutics against SARS-CoV, including assessing half-life, selecting efficacious variants and determining dosage for clinical trials.
JAX is dedicated to supporting the scientific community in its response to the COVID-19 pandemic. View our portfolio of available models for SARS-CoV-2 research.
Genetic Background | Generation |
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N1
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Allele Type | Gene Symbol | Gene Name |
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Targeted (Null/Knockout) | Fcgrt | Fc receptor, IgG, alpha chain transporter |
Allele Type |
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Transgenic (Inserted expressed sequence, Humanized sequence) |
Allele Type |
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Transgenic (Inserted expressed sequence) |
Please see the K18-hACE2 datasheet (Stock No. 034860) for important safety/handling and any updated information on K18-hACE2 mice in SARS-CoV-2 research.
Please note, these mice should be handled in a manner consistent with CDC/ABSA/WHO guidelines for prevention of human infection with the SARS-CoV-2 virus. Proper PPE and handling methods should be used at all times when working with these mice. Additional important guidelines for using SARS-CoV-2 susceptible mouse lines.
Stock No. 034902 K18-hACE2 ; FcRn-/- hFcRn (32) Tg is a multiple mutant strain assembled by breeding Stock Nos. 034860 and 014565. In an attempt to offer popular alleles together, mouse lines may be bred together for purpose of researchers to study and characterize. It should be noted that the phenotype of Stock No. 034902 could vary from that originally described for the individual mouse lines used to assemble it. We may modify the strain description if necessary as published results become available. Each mutant allele is briefly described below [September 2020].
K18-hACE2 transgenic mice express the receptor for severe acute respiratory syndrome (SARS), caused by a coronavirus (SARS-CoV) in airway and other epithelia under control of the human keratin 18 (KRT18) promoter. Specifically, these mice contain 2.5 kb of the KRT18 genomic sequence, including the promoter, and the first intron (with a mutation in the 3' splice acceptor site to reduce exon skipping) and a translational enhancer (TE) sequence from alfalfa mosaic virus, upstream of the human angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 coding sequence (hACE2), followed by exons 6-7 and the poly(A) signal of the human K18 gene. These elements have been found to be necessary for high-level expression and epithelial cell specificity of hACE2, the primary host cell receptor for SARS-CoV. In these mice, from founder line 2, K18-hACE2 transgene expression is evident in airway epithelial cells (but not in alveolar epithelia), as well as in epithelia of other internal organs, including the liver, kidney, and gastrointestinal tract. Recent research indicates that this line may also be useful in studies related to the study of 2019 novel coronavirus (SARS-CoV-2) pathogenesis.
Addition of the FcRn-/- targeted mutation and hFcRn (32) transgene may enhance the human-like protection of humanized IgG potentially making these mice a good model for developing antibody-based therapeutics against SARS-CoV, including assessing half-life, selecting efficacious variants, and determining dosage for clinical trials. Using this model, clinicians may be able to estimate the minimum antibody dose to achieve therapeutic serum concentrations, reducing the need for potentially risky dose-escalation treatments during clinical trials.
The K18-ACE2 transgene, FcRn-/- targeted mutation and hFcRn (32) transgene are able to be maintained as homozygous in their individual mouse lines. However, because the two transgenes are located ~1.9 Mbp apart on chromosome 2, it may be difficult to generate Stock No. 034902 mice with the two transgenes in cis (on the same chromosome). As such, The Jackson Laboratory will maintain and distribute as hemizygous for the K18-ACE2 transgene, hemizygous for the hFcRn (32) transgene and homozygous for the FcRn-/- targeted mutation.
The ~6.8 kb K18-hACE2 transgene was designed with, from 5' to 3', 2.5 kb of genomic sequence, including the promoter, and the first intron (with a mutation in the 3' splice acceptor site to reduce exon skipping) from the human keratin 18 (KRT18) gene, and a translational enhancer (TE) sequence from alfalfa mosaic virus. This was followed by the human angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 (hACE2) coding sequence, and exons 6-7 and the poly(A) signal of the human K18 gene. This transgene was microinjected into fertilized (C57BL/6J x SJL/J)F2 oocytes. K18-hACE2 mice from founder line 2, with 8 copies of the transgene, were subsequently maintained by breeding transgenic mice with C57BL/6 mice for at least two generations (the genetic background of the mice sent to The Jackson Laboratory was later determined to be C57BL/6N via SNP testing). Upon arrival, three backcrosses to C57BL/6J (Stock No. 000664) were then performed to rederive, establish and expand a congenic colony at The Jackson Laboratory as Stock No. 034860.
To create Stock No. 034902, some mice from Stock No. 034860 were bred to FcRn-/- hFcRn (32) Tg mice (Stock No. 014565) carrying a knock-out mutation for the mouse Fc receptor, IgG, alpha chain transporter gene (Fcgrt) on chromosome 7 and a transgene expressing the human FCGRT gene under the control of its own native promoter (hTg32) on chromosome 2 (101,081,712-101,081,713 bp).
In May 2020, analysis commissioned by The Jackson Laboratory determined that multiple copies of the Tg(K18-ACE2)2Prlmn transgene integrated at a single site on chromosome 2 (99,209,508-99,220,724; mouse mm10). An ~11 kb duplication of the host genome (chr2:99,209,508-99,220,724) is present at both ends of the integrated transgene array. Currently, there are no genes annotated in this region. The transgene copy number of the hemizygous mouse is estimated to be 8 full copies (or 12-30 partial copies). As such, The Jackson Laboratory will maintain and distribute as hemizygous for the K18-ACE2 transgene, hemizygous for the hFcRn (32) transgene and homozygous for the FcRn-/- targeted mutation.
Because the two transgenes are located ~1.9 Mbp apart on chromosome 2, it may be difficult to generate Stock No. 034902 mice with the two transgenes in cis (on the same chromosome).
Expressed Gene | FCGRT, Fc fragment of IgG receptor and transporter, human |
---|---|
Site of Expression | The transgene expresses human FCGRT from the native human promoter, and displays a physiological human FCGRT expression pattern (Latvala et al., 2017). |
Site of Expression |
Allele Name | targeted mutation 1, Derry C Roopenian |
---|---|
Allele Type | Targeted (Null/Knockout) |
Allele Synonym(s) | FcRn- |
Gene Symbol and Name | Fcgrt, Fc receptor, IgG, alpha chain transporter |
Gene Synonym(s) | |
Strain of Origin | 129X1/SvJ |
Chromosome | 7 |
Molecular Note | Sequence from exon 1 and part of exon2 was replaced with a PGK-neo cassette. Quantitative PCR of liver cDNA indicated the absence of mRNA. Western blot analysis of neonatal intestinal extracts failed to reveal protein product. |
Allele Name | transgene insertion 32, Derry C Roopenian |
---|---|
Allele Type | Transgenic (Inserted expressed sequence, Humanized sequence) |
Allele Synonym(s) | hFcRn(32) vhFcRn (32) Tg hFcRn (32) Tg; Tg32 |
Gene Symbol and Name | Tg(FCGRT)32Dcr, transgene insertion 32, Derry C Roopenian |
Gene Synonym(s) | |
Promoter | FCGRT, Fc fragment of IgG receptor and transporter, human |
Expressed Gene | FCGRT, Fc fragment of IgG receptor and transporter, human |
Site of Expression | The transgene expresses human FCGRT from the native human promoter, and displays a physiological human FCGRT expression pattern (Latvala et al., 2017). |
Strain of Origin | C57BL/6J |
Chromosome | 2 |
Molecular Note | A 34Kb fragment of a BAC containing the entire human FCGRT , Fc fragment of IgG, receptor, transporter, alpha, gene (approximately 11kb) and approximately 10kb of flanking sequence was sublconed into a SuperCos vector. The resulting cosmid was microinjected into fertilized C57BL/6J mouse eggs. Founder line 32 was established. Transgene insertion occurred on Chr 2. |
Allele Name | transgene insertion 2, Stanley Perlman |
---|---|
Allele Type | Transgenic (Inserted expressed sequence) |
Allele Synonym(s) | K18-hACE2 |
Gene Symbol and Name | Tg(K18-ACE2)2Prlmn, transgene insertion 2, Stanley Perlman |
Gene Synonym(s) | |
Strain of Origin | (C57BL/6J x SJL/J)F2 |
Chromosome | 2 |
Molecular Note | The ~6.8 kb transgene was designed with, from 5' to 3', 2.5 kb of genomic sequence, including the promoter, and the first intron (with a mutation in the 3' splice acceptor site to reduce exon skipping) from the human K18 gene, and a translational enhancer (TE) sequence from alfalfa mosaic virus. This was followed by the human angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 (hACE2) coding sequence, and exons 6-7 and the poly(A) signal of the human K18 gene. The transgene integrated at a single site on chromosome 2 (99,209,508-99,220,724; mouse mm10). An ~11 kb duplication of the host genome (chr2:99,209,508-99,220,724) is present at both ends of the integrated transgene array. Currently, there are no genes annotated in this region. The transgene copy number of the hemizygous mouse is estimated to be 8 full copies (or 12-30 partial copies). Transgene expression is evident in airway epithelial cells (but not in alveolar epithelia), as well as in epithelia of other internal organs, including the liver, kidney, and gastrointestinal tract. |
Stock No. 034902 was created by breeding the Tg(K18-ACE2)2Prlmn [K18-ACE2] transgenic mouse line with the Fcgrttm1Dcr [FcRn-/-] targeted mutation and Tg(FCGRT)32Dcr [hFcRn (32)] transgenic line. The K18-ACE2 transgenic line and the FcRn-/- targeted mutation and hFcRn (32) transgenic line are able to be maintained as homozygous in their individual mouse lines. However, because the two transgenes are located ~1.9 Mbp apart on chromosome 2, it may be difficult to generate Stock No. 034902 mice with the two transgenes in cis (on the same chromosome). As such, The Jackson Laboratory will maintain and distribute as hemizygous for the K18-ACE2 transgene, hemizygous for the hFcRn (32) transgene and homozygous for the FcRn-/- targeted mutation.
The Tg(K18-ACE2)2Prlmn transgene has 8 full copies (or 12-30 partial copies) integrated at a single site on chromosome 2 (99,209,508-99,220,724; mouse mm10). The Tg(FCGRT)32Dcr transgene integrated on chromosome 2 (101,081,712-101,081,713 bp).
Hemizygous for Tg(K18-ACE2)2Prlmn Hemizygous for Tg(FCGRT)32Dcr Homozygous for Fcgrttm1Dcr X Strain 014565 - B6.Cg-Fcgrttm1Dcr Tg(FCGRT)32Dcr/DcrJ and reciprocal
When using the K18-hACE2 ; FcRn-/- hFcRn (32) Tg mouse strain in a publication, please cite the originating article(s) and include JAX stock #034902 in your Materials and Methods section.
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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.
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