A team of researchers at the MU College of Veterinary Medicine Department of Veterinary Pathobiology recently obtained two grants from the National Institutes of Health that focus on finding more effective animal models for COVID-19 research. The team includes members of several of the MU’s unique resources including Elizabeth Bryda, PhD, director of the MU Animal Modeling Core and the NIH-funded Rat Resource and Research Center, Craig Franklin, DVM, PhD, DACLAM and Jim Amos-Landgraf, PhD, co-directors of the NIH-funded Mutant Mouse Resource and Research Center, Aaron Ericsson, DVM, PhD, director of the MU Metagenomics Center, Daniel Davis, PhD, assistant director of the MU Animal Modeling Core, and Deborah Anderson, PhD, and Paul Anderson, PhD, of the Laboratory for Infectious Disease Research.
Franklin and Amos-Landgraf’s project is titled “Optimization of Murine Models of COVID-19 through Gut Microbiota Manipulation.” The goal of this project is to refine the pre-eminent mouse model for COVID research, the K18-hACE2 transgenic mouse so that it is optimally translatable to the human condition. Unlike humans, research mice are raised in pristine environmental conditions and this results in the mouse’s immune system being more similar to a neonatal human than an adult. This is likely because mice are rarely exposed to viral and bacterial diseases that most humans experience as they grow up (e.g. the common cold). To promote the development of an adult immune system in mice, one can expose mice to similar disease-causing agents as well as modify the gut microbiota, the complex communities of thousands of bacteria that inhabit the intestinal tract. Briefly, this project is asking if different microbial communities and previous disease exposures can change the severity of COVID-19 infection in this mouse model. “We’re interested in knowing if it’s the best model it can be,” said Franklin. “Can we refine it to the point where what we see in a mouse is identical to what we see in people?”
The project Bryda is leading, titled, “Generation of Novel Rat Models for the Study of SARS-CoV-2 and COVID-19,” focuses on rats, which may be able to recapitulate human disease better than mice. She is using state-of-the art genetic engineering technology, including the use of CRISPR-Cas9, to create models that have the human ACE2 receptor, the receptor to which SARS-CoV-2 binds. Several new rat strains will be developed that will allow questions about the impact of sex, age, genetic background and levels of expression of the viral receptor on disease symptoms and severity to be explored. “We’re going to use a different strategy, make these genetically engineered rats in a different way than the existing mouse models and hope that they will be a more improved animal model for studying COVID-19,” said Bryda.
Both models rely on being able to infect mice and rats with SARS-CoV-2, the virus that causes COVID-19. To do so requires highly specialized facilities such as the Laboratory of Infectious Disease Research, (LIDR), one of 12 regional biocontainment laboratories funded in part by NIH’s National Institute of Allergy and Infectious Diseases (NIAID) to perform biosafety level three research on infectious agents such as nCoV2-SARS.
The mouse model grant comes in the form of $378,922 and the rat model grant is $203,950. According to the group, they were approached by the NIH to submit applications because of the unique resources here on the MU campus and these played a critical role in ultimately obtaining funding. Franklin summarized this effort saying, “Very few places in the country have the expertise we have here.”
By Nick Childress