K18-hACE2 transgenic mice express human ACE2, the receptor used by the severe acute respiratory syndrome coronavirus (SARS-CoV) to gain entry to cells. The human keratin 18 (KRT18) promoter directs expression to epithelia, including airway epithelial cells where infections typically begin. This model of lethal infection with SARS-CoV mimics the human SARS disease. Recent research indicates this line may be useful in studying antiviral therapies for the 2019 novel coronavirus (SARS-CoV-2) pathogenesis and the disease outbreak COVID-19.
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.
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To learn more about this mouse and other infectious disease models from The Jackson Laboratory please contact firstname.lastname@example.org - 1.800.422.6423 (US) - 1.207.288.5845 (International).
Dr. Stanley Perlman, University of Iowa
Dr. Paul B McCray, University of Iowa
June/July 2020 Update: The Jackson Laboratory has been informed by multiple independent investigators testing these K18-hACE2 mice that, similar to SARS-CoV infection, intranasal infection with SARS-CoV-2 virus results in K18-hACE2 mice with severe illness - reaching criteria for euthanasia ~5-8 days post-challenge [view data from Drs. Perlman and McCray; 1x105 PFU]. This was evidenced by body weight loss, rapid breathing, hunched posture and inactivity as result of infection. Virus titers were reportedly detected in the lungs, brain, kidney, liver and spleen (see additional organs below). Gross pathology of the lungs indicates lesions as a result of infection. Vehicle or untreated control mice showed no signs of illness - gaining weight with a normal appearance.
In addition, K18-hACE2 mice infected with SARS-CoV-2 may replicate the chemokine/cytokine storm traits observed in humans [Oladunni et al. bioRxiv July 2020; 1x105 PFU], and may exhibit viral replication in gut [Rathnasinghe et al. bioRxiv July 2020; 1x104 PFU] and heart [Winkler et al. bioRxiv July 2020; 2.5x104 PFU].
Importantly, some K18-hACE2 animals given lower dose SARS-CoV-2 (2x103 PFU) survived despite significant weight loss [Golden et al. bioRxiv July 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.
Hemizygous mice are viable and fertile. The donating investigator has not attempted to make a homozygous colony.
These K18-hACE2 mice develop a rapidly lethal infection after intranasal inoculation with a human strain of SARS-CoV. Infection begins in airway epithelia, with subsequent alveolar involvement and extrapulmonary virus spread to the brain. Infection results in macrophage and lymphocyte infiltration in the lungs and upregulation of proinflammatory cytokines and chemokines in both the lung and the brain. By days 3 to 5 postinfection, K18-hACE2 mice begin to lose weight and become lethargic with labored breathing. Mice from this founder line are moribund 4 days after inoculation, and all mice are dead 7 days after inoculation. Transgenic expression of hACE2 in epithelia converts a mild SARS-CoV infection into a rapidly fatal disease. [McCray et al. 2007 J Virol. 81:813 (PMID:17079315)]
Please note, these K18-hACE2 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.
This strain ships with a RapID Ear Tag affixed. Learn more about RapID Ear Tag.
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 this congenic colony at The Jackson Laboratory.
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).
|Allele Name||transgene insertion 2, Stanley Perlman|
|Allele Type||Transgenic (Inserted expressed sequence)|
|Gene Symbol and Name||Tg(K18-ACE2)2Prlmn, transgene insertion 2, Stanley Perlman|
|Strain of Origin||(C57BL/6J x SJL/J)F2|
|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.|
When maintaining a live colony, investigators may breed hemizygous mice to wildtype (non-carrier) mice from the colony, or to C57BL/6J inbred mice (Stock No. 000664). It is unknown at this time (January 2020) if homozygous mice are viable and fertile.
When using the K18-hACE2 mouse strain in a publication, please cite the originating article(s) and include JAX stock #034860 in your Materials and Methods section.
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