Texas Biomedical Research Institute

Scientists at Texas Biomed establish a human transgenic mouse model susceptible to SARS-CoV-2 infection

Study provides research community with critical small animal model necessary for researchers developing therapies and vaccines

Newswise — SAN ANTONIO, TEXAS (July 23, 2020) Texas Biomedical Research Institute (Texas Biomed) scientists have added another tool to the COVID-19 toolbelt, validating a new small animal model for studying SARS-CoV-2, the virus that causes COVID-19. Publishing their results preliminarily on the open source journal BioRxiv, researchers at Texas Biomed were among a limited group of scientists nationwide given early access to newly developed transgenic mice that express the human angiotensin-converting enzyme 2 (hACE2) to test whether these mice can be used as a small animal model to assess SARS-CoV-2 infection. Key goals of this study were to determine whether these mice: 1. Can be infected, 2. Reach a similar COVID-19 mortality endpoint as seen in humans with severe COVID-19 disease and 3. Develop immune responses associated with SARS-CoV-2 infection. The paper title is "Lethality of SARS-SoV-2 infection in K18 human angiotensin converting enzyme 2 transgenic mice."

Researchers at Texas Biomed not only found that the human transgenic mice serve as a good model for SARS-CoV-2 infection but also discovered key indicators of an inflammatory immune response (activation of the immune system). Texas Biomed researchers were among the first to discover that this transgenic mouse succumbs to infection, which are critical learnings for future studies. By having a small animal model that mimics a highly susceptible form of human COVID-19 disease, scientists now have the means to perform rapid screening of drug and vaccine candidates and further evaluate SARS-CoV-2 infection progression (pathogenicity). This new tool will play a significant role in reducing the current bottleneck of using nonhuman primates for SARS-CoV-2/COVID-19 vaccine and therapeutic testing.

The team at Texas Biomed, led by Dr. Luis Martínez-Sobrido, Dr. Jordi B. Torrelles and Dr. Joanne Turner, showed detection of virus in the nasal passages, lungs and brain of the K18 hACE2 transgenic mice. These mice also showed significant weight loss before becoming too sick to remain in the study.

“The ACE2 protein has been previously identified as a receptor for SARS-CoV-1, and the expression of the human ACE2 protein in mice renders them susceptible to SARS-CoV-2,” explained Dr. Turner, Professor and Vice President for Research at Texas Biomed. “Scientists have not previously had access to mouse models for SARS-CoV-2 infection studies, because typical lab mice are not susceptible to this virus.”

In this study, scientists showed the K18 hACE2 transgenic mice not only succumbed to the infection but showed systemic (multiple organ) infection with significant virus detected in the nasal passages, lungs, and brain – all organs greatly impacted by SARS-CoV-2 in humans. While minor differences in weight fluctuation were noted between male and female mice after infection, the study did not indicate that gender played a major role in SARS-CoV-2 infectivity or disease progression.

The transgenic mice in this study also developed rhinitis (swelling of the mucus membrane in the nose), pneumonia and associated pulmonary inflammation. Each of these are important indications of viral infection relative to SARS-CoV-2. Essential to the development of an animal model for use in viral studies is identifying the amount of viral exposure necessary to see disease progression that is similar to humans, up to and including mortality. This study is the first to identify the amount of virus necessary during an initial exposure for the transgenic mice to develop severe COVID-19 disease.

“Our data are an important step in increasing our ability to understand SARS-CoV-2 infection and COVID-19 disease in humans,” said Dr. Martínez-Sobrido, Professor at Texas Biomed. “Our studies defined the viral infection dose that results in severe COVID-19 disease and replicated many of the symptoms observed in humans who are admitted to the hospital with severe COVID-19 symptoms.”

In addition to establishing the K18 hACE2 transgenic mouse model supplied by The Jackson Laboratory, researchers also found these transgenic mice were the most susceptible to severe COVID-19 disease progression and produced what is known as a chemokine storm.

Chemokines are small molecules secreted by cells to help signal immune cells to the site of an infection. Chemokines work in concert with cytokines, which are also small molecules or proteins that tell immune cells what to do once they reach the site of infection. The chemokine/cytokine process orchestrates the body’s immune response. A chemokine or cytokine storm can cause an overreaction of the body’s immune system and instead of helping, can cause such a strong response that it becomes detrimental. Determining which chemokines are triggered may be important to development of COVID-19 disease treatments.

“People often succumb to their own body’s immune response to a virus, not the virus itself,” Dr. Turner explained. “There are about 50 known chemokines in the body, so finding a way to block receptors to some of these chemokines would reduce the chemokine/cytokine storm, allowing the body to mount an appropriate immune response.”

Studies on SARS-CoV-2 are completed in biosafety level-3 laboratories under strict regulatory protocols approved by Texas Biomed’s Institutional Biosafety Committee and Institutional Animal Care and Use Committee. Texas Biomed most recently completed a multimillion dollar renovation of BSL-3 space to accommodate the work of Institute scientists, as well as federal and commercial contract studies to test therapeutics and vaccines.

“As noted in the paper, small animal models are more manageable, cost-effective and available for researchers, but we have not had access to a viable mouse model for SARS-CoV-2 infection until now,” explained Dr. Torrelles, Professor, Director of the BSL-3 high-containment program, Lead of the Population Health scientific program and Coordinator of the Coronavirus Working Group at Texas Biomed. “While several nonhuman primate models have been identified to aid in testing vaccines and therapeutics, none have reached endpoints similar to those found in these K18 hACE2 transgenic mice. This mouse model, paired with other small animal models, also in development at Texas Biomed, adds another tool in the toolbox to test therapeutics and fill a critical gap in therapeutic development.”

This study was made possible by community philanthropic support, as well as significant personnel resources dedicating their time and efforts during the pandemic.

SARS-CoV-2 has infected more than 14.7 million people worldwide (3.9 million in the United States) and more than 600,000 people (143,000 in the United States) have lost their lives to this new coronavirus, as of mid-July. In addition to these early-stage studies that are aiding scientists worldwide, researchers at Texas Biomed continue to collaborate with scientists and pharmaceutical companies around the world to move therapies and vaccines through preclinical stages and on to human clinical trials.

“The K18 hACE2 transgenic mouse model developed at Texas Biomed represents an excellent tool to identify both prophylactics (vaccines) and therapeutics (antivirals) to combat SARS-CoV-2 infection and associated COVID-19 disease,” Martínez-Sobrido added.

With the Institute’s focus on infectious diseases and dedication to both basic and translational research, Texas Biomed currently has more than two dozen COVID-19-related studies in process and continues to shepherd partnerships that lead to high-quality science. To learn more visit www.txbiomed.org/coronavirus.

 

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