A New Mouse Model for SARS-CoV-2 Studies Beyond the Respiratory System
Five years since the onset of the COVID-19 pandemic, the scientific community delved deep into the mysteries of
the SARS-CoV-2 virus, to understand its impact on our health and develop antiviral therapies and vaccine.
We know that SARS-CoV-2 virus enters human cells primarily through the angiotensin-converting enzyme 2
(hACE2) receptor, which is abundant in various organs such as the lungs, intestines, heart, kidneys, and more. In addition to acute symptoms, the virus can also causes extrapulmonary manifestations, including cardiovascular issues, kidney injury, and neurological symptoms, as well as complications like thrombosis and multi-organ dysfunction. Animal models, particularly genetically modified mice with human ACE2 receptors, have been crucial for studying SARS-CoV-2. However, existing models primarily focus on the respiratory system, leaving gaps in understanding
systemic organ involvement
Generation of a New Conditional Model
To address this, a new conditional mouse model called Rosa26 creERT2/chACE2 has been developed at the Institute of
Molecular Genetics of the Czech Academy of Sciences. The scientific publication (Gambini, 2025) describes how Rosa26 creERT2/chACE2 model was created, using a tissue-specific Cre-driver mouse strain or tamoxifen inducible Cre-driver to allow precise tissue-specific expression of
hACE2.
After Tamoxifen administration (to induce hACE2 expression), mice were infected intranasally with the SARS-
CoV-2 strain B.1 at various doses. Infection was monitored daily, and mice were euthanized upon reaching humane
endpoints (e.g., 25% body weight loss or other severe symptoms).perreactivity or inflammation in controls.
Characterization of the Rosa26 creERT2/chACE2 Mice
Several assays and analysis were performed:
- Plaque Forming Assay, from lungs, brain, heart, liver, kidney, and small intestine tissues
- RNA Extraction and cDNA Conversion
- Real-Time qPCR
- Flow Cytometry analysis
- Lung Function Assessment, using the flexiVent system
- Histopathology and Immunohistochemistry
Data were analyzed using a linear mixed model to evaluate the effects of treatment and sex on the results, with
random effects for individual animals
Results
The Rosa26 creERT2/chACE2 transgenic mice express human ACE2 (hACE2), the primary receptor for SARS-CoV-2,
and exhibit widespread hACE2 expression in multiple organs after tamoxifen administration, enabling a broader
understanding of SARS-CoV2.
Upon intranasal infection with varying viral doses, the disease severity was found to be dose-dependent, with higher
viral loads causing fatal infections. Males were more susceptible, exhibiting higher mortality and more severe
symptoms than females.
Lung function analysis with flexiVent showed that infected males had increased lung resistance and stiffness,
indicating lung obstruction and inflammation, whereas females showed milder changes.
Intranasal infection led to more severe disease compared to intratracheal infection, with intranasally infected mice
showing significant body weight loss and early onset of symptoms. Notably, intranasal infection facilitated viral
spread to the brain, while intratracheal infection resulted in milder disease and limited viral replication in the brain.
Immune responses in the mice varied between infection routes. Intranasal infection triggered a stronger innate
immune response with increased neutrophils and effector cytotoxic T cells, while intratracheal infection showed a
milder immune response. These findings suggest that the route of infection significantly affects disease progression
and immune responses, with intranasal infection leading to more severe outcomes.
Conclusion
This new mice model provides a useful tool for studying the multisystemic impacts of SARS-CoV-2 infection,
including its neurological effects, immune responses, and potential for long-term protection against reinfection.
Future research could further explore these aspects, especially focusing on different variants and brain regions
affected by the virus
References
Gambini, F., Arbon, D., Nickl, P. et al. New mouse model for inducible hACE2 expression enables to dissect SARS-CoV-2 pathology beyond the respiratory system. Mamm Genome (2025). https://doi.org/10.1007/s00335-025-10115-1
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