USU Scientists Contribute to Two Important COVID-19 Studies

This week, the results of research collaborations with Utah State University Professor Zhongde Wang’s lab have been published in two journals, one aiding in understanding the severe disease course of COVID-19 and the other investigating how mutations in SARS-CoV-2 — specifically the Omicron variant — allow the virus to enter and infect human cells. In both collaborations, a key factor was the use of a transgenic hamster model developed in Wang’s lab.

The transgenic hamster model carries and expresses the human ACE2 gene that encodes the cell membrane proteins that serve as receptors for SARS-CoV-2 infections. The study described in Nature identifies the hamsters as the first animal model that is highly susceptible to the Omicron variant, developing weight loss and other signs of the disease, including mortality. “SARS-CoV-2 Omicron Virus Causes Attenuated Infection in Mice and Hamsters”appears in the journal Nature.

The other study, done in collaboration with U.S. Army scientists, showed that transgenic expression of the human ACE2 gene renders the hamster highly susceptible to the previous strains of SARS-CoV-2 and lethal disease develops. This model system will aid in a more comprehensive understanding of the severe disease course of COVID-19, including the virus’s interaction with the central nervous system, and will support the advancement of vaccines and therapeutics targeting the virus. “Hamsters Expressing Human Angiotensin-converting Enzyme 2 Develop Severe Disease following Exposure to SARS-CoV-2” was published in mBIO, the journal of the American Society for Microbiology.

“This unique hamster model is proving invaluable in the development of effective countermeasures to prevent transmission of SARS-CoV-2,” Wang said. “Furthermore, studies with this animal model could provide insights into the evolution of SARS-CoV-2 and allow us to be prepared for emerging new variants that could be more transmissible and virulent.”

Studies in animal models are a crucial aspect of developing treatments to combat disease because any prospective treatment must be tested in multiple non-human animals before they can move on to clinical trials in humans. Discovering how a virus enters a cell and the mechanisms it uses to cause disease are important steps in creating treatments.

Wang, a professor of animal science in USU’s College of Agriculture and Applied Sciences, noted that his research team takes animal welfare as an extremely serious concern and only the minimum numbers of animals required are used. In addition, all procedures are evaluated and approved by Institutional Animal Care and Use Committees.

“It is essential to use these animals in vaccine studies before trials can be done in human subjects,” Wang said. “Because the hamsters are designed specifically to react to disease challenges more like humans, fewer experiments are necessary to verify results, which expedites the process and can reduce the number of animals used in research.”

The paper in Nature notes that the effectiveness of existing vaccines has been jeopardized as variants of the SARS-CoV-2 virus have emerged in the past several months. The variants have developed mutations in the spike protein on the surface of the virus. The spike protein allows the virus to penetrate host cells and cause infection. The omicron variant, which emerged in November of 2021, has the largest number (>30) of changes, deletions, or insertions in the spike protein that have been described to date by scientists worldwide. The study was done by an international team of scientists supported by the SARS-CoV-2 Assessment of Viral Evolution Risk Assessment Program, working to provide real-time risk assessments of emerging variants.

The paper in mBIO, authored by Joseph W. Golden and colleagues at the U.S. Army Medical Research Institute of Infectious Diseases, notes that animal models that mimic the course of human disease are essential as the virus continues to change and impact humans in very different ways. An important aspect of these studies is to understand how the virus can produce severe and potentially deadly disease in a small percentage of the population.

“Working with Utah State University and leveraging their transgenic animal technology, together with USAMRIID’s emerging infectious disease research expertise, has allowed us to more comprehensively understand the pathophysiology of SARS-CoV-2,” Golden said.

While SARS-CoV-2 most typically causes a respiratory infection, more evidence is suggesting that there can be a neurological aspect of COVD-19 that is poorly understood. This novel hamster system leads to infection of the central nervous system, including the brain and spinal cord, in addition to lung injury. Additionally, the authors found that uninfected control animals in proximity to infected animals also had the virus, indicating that this model system is highly sensitive to SARS-CoV-2 infection and may be ideal for studying viral spread between hosts.

“This hypersensitive hamster model might be particularly useful for variants of concern that cause mild disease in wild-type hamsters,” said Jay W. Hooper, the mBIO paper’s senior author.

Members of the research team in Wang’s lab who worked on the development of the transgenic hamster lines and are co-authors on the papers include post-doctoral researchers Rong Li and Yanan Liu and technician Deanna Larson. In addition, several graduate and undergraduate researcher assistants who have moved on in their academic and career pursuits are also among the papers’ co-authors.