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Live Imaging and Quantification of Viral Infection in K18 hACE2 Transgenic Mice Using Reporter-Expressing Recombinant SARS-CoV-2
Published on: November 5, 2021
SARS-CoV-2 infection in the lungs of human ACE2 transgenic mice causes severe inflammation, immune cell infiltration,
Abstract:
Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) emerged in late 2019 and has spread worldwide resulting in the Coronavirus Disease 2019 (COVID-19) pandemic. Although animal models have been evaluated for SARS-CoV-2 infection, none have recapitulated the severe lung disease phenotypes seen in hospitalized human cases. Here, we evaluate heterozygous transgenic mice expressing the human ACE2 receptor driven by the epithelial cell cytokeratin-18 gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lung tissues with additional spread to other organs. Remarkably, a decline in pulmonary function, as measured by static and dynamic tests of respiratory capacity, occurs 4 days after peak viral titer and correlates with an inflammatory response marked by infiltration into the lung of monocytes, neutrophils, and activated T cells resulting in pneumonia. Cytokine profiling and RNA sequencing analysis of SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with prominent signatures of NF-kB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection recapitulates many features of severe COVID-19 infection in humans and can be used to define the mechanistic basis of lung disease and test immune and antiviral-based countermeasures.
Insights
Transgenic mice expressing human ACE2 receptors effectively model severe COVID-19 lung disease. This model shows significant viral replication, pulmonary dysfunction, and an inflammatory response, aiding research into SARS-CoV-2 pathogenesis.
Area of Science:
- Virology
- Immunology
- Pathology
Background:
- The COVID-19 pandemic, caused by SARS-CoV-2, lacks animal models that fully replicate severe human lung disease.
- Existing models do not adequately capture the critical respiratory phenotypes observed in hospitalized patients.
Approach:
- Evaluated K18-hACE2 transgenic mice, which express human ACE2 receptors under the cytokeratin-18 promoter, as a model for SARS-CoV-2 infection.
- Administered SARS-CoV-2 via intranasal inoculation and assessed viral load, pulmonary function, inflammatory markers, and gene expression.
Key Points:
- K18-hACE2 mice exhibited high viral loads in lung tissue and systemic spread.
- Significant decline in pulmonary function correlated with inflammation, including monocyte, neutrophil, and T cell infiltration, leading to pneumonia.
- Analysis revealed a robust innate immune response, including NF-kB signaling, interferon pathways, and leukocyte activation.
Conclusions:
- The K18-hACE2 mouse model accurately recapitulates key features of severe COVID-19 lung disease in humans.
- This model is valuable for elucidating the mechanisms underlying SARS-CoV-2-induced lung pathology.
- It serves as a crucial platform for evaluating antiviral therapies and immune-based countermeasures.
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