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A CRISPR-targeting approach was used to insert human ACE2 DNA consisting of 5' UTR and coding sequence (exons 2-19) fused to mouse Ace2 3' UTR, replacing the endogenous gene stretching from the 5' UTR to the starting ATG in exon 2.
The humanized knock-in ACE2 (hACE2) mice express ACE2 at a level and pattern similar to Ace2 expression in wild type mice. In contrast, mouse Ace2 expression is 30-40 fold lower in the humanized knock-in ACE2 mouse in which the mouse allele was interrupted by the human coding sequence. To validate that hACE2 mice are susceptible to SARS-CoV-2, 9 male and 9 female 8-week-old mice were challenged intranasally with 105 plaque forming units (PFU) of a delta lineage strain of SARS-CoV-2 (B.1.617.2, hCoV-19/USA/PHC658/2021). The dose was pre-determined to be uniformly lethal in B6.Cg-Tg(K18-ACE2)2Prlmn/J (K18) mice which were used as positive controls (n=6). Mock inoculated hACE2 mice (n=7) treated with PBS served as negative controls. Mice were monitored daily for weight loss and disease signs for 10 days. Parallel patterns of transient weight decreases were observed on days 2-5 for all groups, with more pronounced weight loss in K18 mice which were all euthanized by day 6 due to greater than 20% loss of starting body weight. Weight loss was not limited to one biological sex and did not correlate with starting weight. Aside from transient weight loss, hACE2 mice showed no disease signs (ataxia, e.g.), contrasting with K18 mice which were severely lethargic on days 5 and 6. Infectious SARS-CoV-2 levels were assessed by testing tracheal swabs on days 1-6, and serum, lung, heart, kidney, and brain from a subset of mice euthanized on days 2, 4, and 6. Infectious SARS-CoV-2 was not detected in any serum, heart, or kidney sample from any mouse, but was detected in just 1 tracheal swab from a hACE2 mouse on day 1, which contrasted with SARS-CoV-2 detection from all K18 mice on day 1 and in most on day 2. SARS-CoV-2 levels in lungs of hACE2 and K18 mice were similar, with highest titers on day 2. Unlike in K18 mice, no hACE2 mouse contained detectable infectious virus in brain. Detection of SARS-CoV-2 RNA in tracheal swabs on at least 2 days from days 1-3 correlated with detection of infectious virus in lungs in both KI hACE2 and K18 mice. These results demonstrate that the proposed experimental conditions reproducibly cause non-lethal SARS-CoV-2 infection in hACE2 mice and that measuring SARS-CoV-2 RNA in tracheal swabs can be used as a minimally invasive approach to confirm infection.
Colony Surveillance Program and Current Health Reports
Limited quantities of breeder mice (up to 2 males and 2 females or 4 mice) per investigator per month are available from a live colony, usually available to ship in under 12 weeks. Larger quantities may be available, please contact the distributing center directly at mmrrc@ucdavis.edu for more details.
Cryopreserved material may be available upon request, please inquire to mmrrc@ucdavis.edu for more information.
A license from third party patent owner(s) may be required for for-profit entities to use mouse models derived from CRISPR-Cas9 technologies and it is the Users sole responsibility to determine whether such a license is necessary.
Distribution of this strain requires submission of the MMRRC Conditions of Use (COU). A link to the COU web form will be provided via email after an order has been placed; the form should be completed then or the email forwarded to your institutional official for completion.
Additional charges may apply for any special requests. Shipping costs are in addition to the basic distribution/resuscitation fees. Information on shipping costs and any additional charges will be provided by the supplying MMRRC facility.
1 The distribution fee covers the expense of rederiving mice from a live mouse; you will receive the resulting litter. The litter will contain at minimum one mutant carrier; the actual number of animals and the gender and genotype ratios will vary. (Typically, multiple breeder pairs can be established from the recovered litter.) Prior to shipment, the MMRRC will provide information about the animals recovered. If you anticipate or find that you need to request specific genotypes, genders or quantities of mice in excess of what is likely from a resuscitated litter, you may discuss available options and pricing with the supplying MMRRC facility.
2 An aliquot contains a sufficient number of embryos (in one or more vials or straws and based on the transfer success rate of the MMRRC facility) to transfer into one to three recipients. The MMRRC makes no guarantee concerning embryo transfer success experienced in the recipient investigator's laboratory. Neither gender nor genotype ratios are guaranteed.
3 An aliquot is one straw or vial with sufficient sperm to recover at least one litter of mice, as per provided protocols, when performed at the MMRRC facility. The MMRRC makes no guarantee concerning the success of these procedures when performed outside the MMRRC facilities.
4 The distribution fee covers the expense of resuscitating mice from the cryo-archive; you will receive the resulting litter. The litter will contain at minimum one mutant carrier; the actual number of animals and the gender and genotype ratios will vary. (Typically, multiple breeder pairs can be established from the recovered litter.) Prior to shipment, the MMRRC will provide information about the animals recovered. If you anticipate or find that you need to request specific genotypes, genders or quantities of mice in excess of what is likely from a resuscitated litter, you may discuss available options and pricing with the supplying MMRRC facility.