Human ACE2 transgenic pigs: A large animal model for Covid-19
Lead Research Organisation:
University of Edinburgh
Department Name: The Roslin Institute
Abstract
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.
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.
Organisations
| Description | The first step in this procedure was the generation of a lentivirus vector that expresses human ACE2. This was achieved through standard cloning approaches and expression of ACE2 was confirmed by western blot analysis and RT-qPCR. High titre preps were generated, Validated and check for toxicity after injection into pig zygotes. Intiial pig surgeries have been performed, implanting lentivirus transducer zygotes. we are currently waiting to see if the recipient pigs are pregnant. WE have now confirmed the generation of hACE2 expressing transgenic pigs. hACE2 expression was confirmed by RT-qPCR and primary cells have been generated for further charaterisation. Pigs hvae been selected based on hACE2 expression for further breeding. Piglets from the F1 cohort will be charaterised for hACE2 expression then used for an initial proof of concept challenge study, to determine whether they are susceptible to infection with SARS-CoV-2. |
| Exploitation Route | If the challenge study is successful and the pigs are shown to be susceptible, this will open the field to multiple potential studies, including vaccine studies, immunology studies, antiviral studies and pathogenesis studies. |
| Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |