K18-HACE2 Mice as a SARS-CoV-2 Infection Model

A Humanized Mouse Model for Studying Severe COVID-19 and Pulmonary Dysfunction

Developing reliable animal models of SARS-CoV-2 infection has been essential for understanding COVID-19 pathogenesis and evaluating vaccines and therapeutics. A study published in Nature Immunology demonstrated that K18-hACE2 mice can develop severe pulmonary disease following SARS-CoV-2 infection, making them a valuable preclinical model for COVID-19 research.

Why Use K18-hACE2 Mice for SARS-CoV-2 Research?

Conventional mice are poorly susceptible to SARS-CoV-2 because the virus does not efficiently interact with the mouse ACE2 receptor. K18-hACE2 mice overcome this limitation by expressing human ACE2 (hACE2) under the cytokeratin-18 promoter.

Following infection, these mice develop disease features that resemble severe human COVID-19, including viral replication, pulmonary inflammation, pneumonia, and impaired lung function.

SARS-CoV-2 Infection and Lung Disease

In the study, K18-hACE2 mice infected with SARS-CoV-2 developed high viral levels in the lungs and a strong inflammatory response. Histopathology revealed immune cell infiltration and significant pulmonary damage, accompanied by substantial body weight loss.

Importantly, the model also demonstrated measurable changes in respiratory mechanics, providing functional evidence of SARS-CoV-2-induced lung injury.

Measuring COVID-19 Lung Dysfunction with flexiVent

The flexiVent system was used to assess pulmonary function at multiple time points following SARS-CoV-2 infection.

By 7 days post-infection, infected mice showed:

• Reduced inspiratory capacity
• Increased respiratory system resistance (Rrs)
• Increased respiratory system elastance (Ers)
• Reduced static compliance (Cst)
• Increased tissue damping and tissue elastance

   species demonstrate the ability to get infected with SARS-CoV-2 but do not present typical symptoms seen in the human disease. Hamste

  

Figure 1: from A SARS-CoV-2 Infection Model in Mice Demonstrates Protection by Neutralizing Antibodies These findings indicate increased airway and tissue resistance, reduced lung compliance, and stiffening of the lung parenchyma.

The relatively limited change in Newtonian resistance (Rn) suggests that SARS-CoV-2-associated dysfunction primarily affected the peripheral lung and parenchyma, consistent with pulmonary pathology observed in severe COVID-19.

A Valuable Model for COVID-19 Research

The K18-hACE2 mouse model provides researchers with a reproducible system for studying SARS-CoV-2 pathogenesis, pulmonary inflammation, and respiratory dysfunction.

Combining viral and histological assessments with quantitative lung function measurements using flexiVent provides a comprehensive approach to evaluating disease progression and testing potential vaccines and therapeutics.

Key Takeaways

• K18-hACE2 mice are susceptible to SARS-CoV-2 infection and develop severe pulmonary disease.
• Infection produces pulmonary inflammation, pneumonia, and lung injury.
• flexiVent enables detailed assessment of SARS-CoV-2-induced respiratory dysfunction.
• Changes in resistance, elastance, and compliance demonstrate significant impairment of lung mechanics.
• The model is valuable for studying COVID-19 pathogenesis and evaluating potential vaccines and treatments.