Modeling SARS-CoV-2 Pathogenesis in Transgenic Mouse Systems

Transgenic mouse systems have become indispensable tools for dissecting the mechanisms of SARS-CoV-2 infection, replication and host response. By introducing human genes such as the angiotensin-converting enzyme 2 (ACE2) receptor or the protease TMPRSS2 into the murine genome, researchers have overcome the natural resistance of mice to the virus. These models reproduce key features of human COVID-19, including viral entry through airway epithelia, pulmonary inflammation, immune dysregulation and, in some cases, neuroinvasion. Advances in genetic engineering—ranging from tissue-specific promoters to knock-in constructs activated by Cre-recombinase—have enabled precise control of viral tropism and severity. Mouse-adapted viral strains carrying spike protein mutations further refine the simulation of human pathogenesis. Collectively, transgenic mouse platforms offer a rapid, cost-effective and ethically tractable means to evaluate antiviral agents, immune correlates of protection and host-directed therapies against SARS-CoV-2.

Research from Nature Portfolio

Studies have delineated inflammatory pathways that drive disease severity in hACE2 transgenic mice. In a model expressing the K18 promoter, deficiency of the transcription factor Foxo1 in CD4+ T cells markedly reduced interleukin-9 production and protected against airway inflammation, while directed IL-9 blockade attenuated lung injury and viral spread. Investigations of emerging variants in human ACE2-expressing mice revealed that the Omicron lineage induces milder weight loss, lower viral loads and reduced pulmonary pathology compared with ancestral strains, underscoring variant-dependent shifts in pathogenicity. Foundational work with K18-hACE2 mice demonstrated uniform lethality, widespread cytokine and chemokine storms in lung and brain tissues, and the suitability of this model for probing severe neurological and respiratory manifestations of COVID-19.

Modeling SARS-CoV-2 Pathogenesis in Transgenic Mouse Systems publication trend

The graph below shows the total number of articles in modeling sars-cov-2 pathogenesis in transgenic mouse systems across all publications each year (not limited to Nature Index journals).

Technical terms

Transgenic mouse: A laboratory mouse genetically engineered to carry and express foreign genes in its genome.

Human ACE2: A human cell-surface receptor for SARS-CoV-2 spike protein that mediates viral entry.

TMPRSS2: A serine protease that cleaves the viral spike protein, facilitating membrane fusion and entry of SARS-CoV-2.

Mouse-adapted strain: A variant of SARS-CoV-2 engineered or selected to replicate efficiently in mice.

Cre-recombinase: An enzyme that recognises loxP sites to induce site-specific genetic recombination, enabling conditional gene expression.

References

1. SARS-CoV-2 immunity in animal models. Cellular & Molecular Immunology (2024).
2. IL-9 aggravates SARS-CoV-2 infection and exacerbates associated airway inflammation. Nature Communications (2023).
3. SARS-CoV-2 Omicron virus causes attenuated disease in mice and hamsters. Nature (2022).
4. Lethality of SARS-CoV-2 infection in K18 human angiotensin-converting enzyme 2 transgenic mice. Nature Communications (2020).
5. Generation of a lethal mouse model expressing human ACE2 and TMPRSS2 for SARS-CoV-2 infection and pathogenesis. Experimental & Molecular Medicine (2024).
6. A tissue specific-infection mouse model of SARS-CoV-2. Cell Discovery (2023).
7. Characterization and structural basis of a lethal mouse-adapted SARS-CoV-2. Nature Communications (2021).