Human ACE2 transgenic pigs: A large animal model for Covid-19

Animal models which accurately reflect Covid-19 disease will be critical for vaccine development, antiviral testing and pathogenesis studies. Successful application of in vivo studies will depend on a combination of approaches from multiple animal models. There are a number of animal models for studying Covid-19. 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 are the most comparable model to human infections. While each of these models has advantages, there are also drawbacks. Rodent models do not accurately reflect human disease and their gross morphology and immunological responses are divergent from humans. Ferrets lack molecular tools, while non-human primates are expensive and restricted to a few institutions around the world. There is a growing appreciation of the use of livestock species as models for human disease. We propose developing pigs as large animal models for Covid-19. Their use is less restrictive compared to non-human primates and associated molecular tools are improving rapidly. As pigs are not susceptible to SARS-CoV-2, we will generate transgenic pigs that express the human angiotensin-converting enzyme 2 (ACE2), the main receptor for SARS-CoV-2 and main determinant of species susceptibility. As well as being an excellent model for vaccine development and antiviral testing, a viable pig model of Covid-19 would be extremely valuable to answer important questions of viral pathogenesis such as; which cells, tissues and organs are infected and when? How does the virus spread within the body? Does the virus infect the central nervous system and what are the long-term consequences of cardiovascular involvement? What factors effect spread between hosts? These studies will not only be critical in our ability to successfully respond to the current pandemic, but will be important for our ability to respond to future pandemics.