Human ACE2 transgenic pigs as a large animal model for COVID-19

Background

During the COVID-19 pandemic, there was an urgent push for the development of animal models that accurately reflected the disease, pathology and host responses to the virus. 

Rodent models, including aged mice, mice engineered to express hACE2 and mice infected with mouse-adapted virus, have all been used. Golden Syrian hamsters are also susceptible to human coronaviruses. Ferrets are susceptible to infection and have shown promise as models of viral spread. Non-human primates have also been used. There are advantages and disadvantages to each model. 

However, rodent models are evolutionarily divergent from humans and have grossly different anatomy and biology. Non-human primate models are far more similar to humans; however, their use is restricted to a few institutes worldwide.

Pigs are increasingly recognised as valuable models for human disease due to their genetic, anatomical, physiological, and immunological similarities to humans. They also present a more ethically viable alternative to non-human primates. 

However, pigs are not susceptible to SARS-CoV-2 infection, which limits their utility as a model. To address this, LARIF developed transgenic pigs expressing human ACE2 that are susceptible to SARS-CoV-2 infection.

At LARIF

The expertise and facilities within LARIF allowed for a custom lentivirus expressing hACE2 under the Keratin 18 promoter to be micro-injected into zygotes, which were then surgically implanted into five surrogate gilts. 

The procedure was successful on the first try, reducing the number of animals needed for the study and demonstrating the rapid development of a biomedical model for a human infectious disease during a global crisis.

Impact

To our knowledge, this is the only large animal model of moderate-to-severe COVID-19, making it unique in the field, and the clinical signs and disease pathology are more consistent with human disease than in other animal models. 

While effective vaccinations have reduced the severity of COVID-19, the disease is still a major issue for vulnerable populations. So characterising the disease mechanisms during COVID-19 remains important for future pandemic preparedness, and the human ACE2 pigs represent a unique and highly relevant model for such studies.

Publications

Human ACE2 transgenic pigs are susceptible to SARS-CoV-2 and develop COVID-19-like disease. 

Chau, LF, Lillico, S, Opriessnig, T. et al. 

2025, Nat Commun 16, 766.