When the SARS-COV-2 virus, which has been shown to cause COVID-19, swept the world in 2020, JAX researchers saw the immediate need for optimal animal models to study viral effects and develop effective therapeutics. As a result, they created this comprehensive portfolio of COVID-19 models. This portfolio offers a wide range of models to give you the ideal solution for your research and therapeutic development needs, from preventing infection to examining long-term viral effects.
Mice have historically been the model of choice for preclinical studies due to their biological features and ease of use. The SARS-COV-2 virus that has been shown to cause COVID-19 underscored the need to utilize optimal animal models to develop much-needed therapies. As the SARS-CoV-2 virus does not infect wild-type mice, the new portfolio of mouse models is even more crucial now that they have been shown to be susceptible to the SARS-COV-2 virus.
Studies show that SARS-CoV enters the human body by binding to human angiotensin-converting enzyme 2 (ACE2). However, due to structural differences in mouse ACE2 compared to human ACE2 proteins, the SARS coronaviruses exhibit poor tropism characteristics for mouse tissues and is inefficient at infecting mice. This mouse model portfolio provides researchers with the much-needed strains to propel COVID-19 research and drug discovery and therapeutic development.
This model was the first strain available from JAX that could be infected with the SARS-CoV-2 virus. Viral infection was characterized by weight loss, rapid breathing, hunched posture, inactivity, and lung lesions verified during post-infection pathology. Further analysis of this model also exhibited chemokine/cytokine storm traits, like what is observed in humans, with viral replication in both the gut and heart.
This model would be advantageous for high-throughput screening for therapeutic candidate testing, including patient convalescent plasma, vaccines, monoclonal antibodies, and studies involving dual infection of SARS-CoV-2 and influenza. It’s important to note that these mice respond to a viral challenge in a dose-dependent manner, which allows for the study of both severe acute respiratory disease and the long-term effects from low dose, mild infections.
In an effort to provide researchers with an alternative to the K18-hACE2 model on the C57/BL6J background (see model above), JAX also developed a model on the BALBc genetic background. This model expresses human hACE2 and utilizes the human keratin 18 promoter, which directs expression to the epithelia. This model would be useful in studying antiviral therapies to COVID-19 and SARS.
And similar to the two strains above, this model also utilizes the hACE2 gene but utilizes the JAX NSG™ genetic background. As this model combines the keratin 18 promoter and the severe immunodeficiency of the NSG background, it may result in reduced immune response and increased susceptibility to SARS-CoV viral infection.
This transgenic model expresses both the human ACE2 and human FcRn genes and lacks the endogenous mouse FcRn gene. As with the other K18-hACE2 model, this strain also allows for the SARS-CoV-2 virus to enter its target cells, and the expression of the human FcRn gene in place of the mouse gene enables researchers to test antibody stability in vivo (Avery et al., 2016). This strain is ideal for researchers to predict monoclonal antibodies’ ability to block the spreading of SARS-CoV-2 infection in vivo.
This strain expresses human ACE2 under the direction of the endogenous regulatory elements of the mouse ACE2 locus. High SARS-CoV-2 viral variants loads were detected in the nasal conchae and lungs for hACE2-K1 mice, indicating that this model supports efficient viral replication after infection. Additionally, strategically placed loxP sites around the hACE2 cDNA sequence allows for cre-recombination in a tissue-specific manner to delete hACE2 where desired. This model may be useful in examining the effects of SARS-CoV-2 infection one tissue or cell type while protecting another, and with decreased severity, may elucidate long-term effects of viral exposure.
This unique model expresses both the human ACE2 gene and a mutation in Ifnar1, which results in the gene being knocked out. Those with defective INFAR1 have shown increased susceptibility to SARS-CoV-2. As with the other models, expression of human ACE2 allows for infection of mice with the SARS-CoV-2 virus, while the knockout of Ifnar1 may result in reduced immune response and increased susceptibility to SARS-CoV-2 viral infection during preclinical studies. This model may be useful for researchers studying infection or the effects of potential therapies in immunocompromised patients.
This model has the endogenous mouse Ace2 gene replaced by the human ACE2 version. This receptor can be used by several coronaviruses, including SARS-CoV-1 and SARS-CoV-2. This strain may be useful for studying antiviral therapies to COVID-19.
This latest portfolio addition is just another example of the JAX commitment to the global research community in the shared quest to improve health. The new mouse models, available exclusively from JAX, have been shown to be susceptible to the SARS-COV-2 virus and will enable researchers to meet their milestones from vaccine development to treatments and therapies. With various models to choose from, researchers can access the most optimal model for their study. Be sure to learn more about these and other precision models and powerful in vivo services that JAX offers. Speak to a JAX expert about your specific research needs and how JAX solutions can enable you to reach your milestones faster and with more accurate data.
Avery LB, Wang M, Kavosi MS, et al. (. Utility of a human FcRn transgenic mouse model in drug discovery for early assessment and prediction of human pharmacokinetics of monoclonal antibodies. MAbs. 2016 Aug-Sep;8(6):1064-78. doi: 10.1080/19420862.2016.1193660. Epub 2016 May 27. PMID: 27232760; PMCID: PMC4968115.