Scientists have created six strains of humanized mice that can be instrumental for researching COVID-19 in humans.
Scientists at La Jolla Institute for Immunology (LJI) have developed six lines of humanized mice that can serve as valuable models for studying human cases of COVID-19.
A recent study published in eBioMedicine highlights the significance of these mouse models for COVID-19 research. The cells of these mice have been modified to incorporate two critical human molecules that play a role in the infection process of SARS-CoV-2 in humans. Furthermore, these humanized mice have been developed on two distinct immunological backgrounds. This advancement can enhance our understanding of how SARS-CoV-2 travels within the body and why individuals display varied symptoms of COVID-19.
“These mouse models allow us to replicate relevant SARS-CoV-2 infections and vaccination scenarios, enabling detailed analysis of various tissues (not limited to just blood) over different timeframes post-infection or vaccination,” explains LJI Professor Sujan Shresta, Ph.D., co-leading the research alongside LJI Histopathology Core Director Kenneth Kim, Dipl. ACVP, and the late Kurt Jarnagin, Ph.D. from Synbal, Inc.
Thus far, these new mouse models have provided scientists with a clearer understanding of how SARS-CoV-2 impacts humans, and they are accessible to the broader COVID-19 research community.
“This effort aligns with LJI’s goal of enhancing global pandemic preparedness,” states Shresta.
Mouse models are essential for infection research
Shresta’s lab is recognized for generating mouse models for investigating immune reactions against infectious diseases like dengue and Zika viruses. In 2021, her team collaborated with Synbal, Inc., a preclinical biotech firm from San Diego, CA, to create multi-gene, humanized mouse models tailored for COVID-19 research, under the support of Synbal CEO and LJI Board Member David R. Webb, Ph.D.
Shresta and Jarnagin worked together to produce mice that express either human ACE2, human TMPRSS2, or both, using the C57BL/6 and BALB/c genetic backgrounds. “Researchers have observed that these two mouse genetic backgrounds provoke diverse immune responses,” notes Shresta.
This flexibility enables scientists to explore two critical areas: how each molecule influences infection by various SARS-CoV-2 variants, and how the host’s genetic makeup may affect disease progression and the immune response after infection with different variants.
Examining infected tissues closely
The team examined how these models reacted to actual SARS-CoV-2 infections. LJI Postdoctoral Fellow Shailendra Verma, Ph.D., utilized the High Containment (BSL-3) Facility at LJI to gather tissue samples from various mouse strains after exposure to the virus.
“This project wouldn’t have been feasible without a BSL-3 facility here at LJI,” remarks Shresta, who has collaborated with LJI’s Department of Environmental Health and Safety to carry out many advanced studies in the facility.
Following this, Kim, a board-certified pathologist, scrutinized the tissue samples, comparing them to pathological results from humans diagnosed with COVID-19.
Kim’s evaluation indicated signs of SARS-CoV-2 infection in the lungs, which are the tissues most susceptible to the virus in humans. He also observed mouse immune cells reacting to the infection in a manner akin to the human immune response.
By describing these reactions in the new mouse models, the researchers have laid the groundwork for understanding the immune diversity associated with SARS-CoV-2 induced diseases.
“While no animal model is flawless, we strive to develop models that closely replicate human disease and immune reactions,” adds Shresta.
The newly developed mouse models could be crucial for investigating responses to new SARS-CoV-2 variants and forthcoming coronaviruses that may cause pandemics.
“These models not only support current COVID-19 investigations but will also be beneficial if future coronaviruses emerge that use the ACE2 receptor and/or TMPRSS2 for entering human cells. This preparedness, with the strains being derived from two genetic backgrounds, is invaluable,” says Kim.
Other contributors to the study, titled “Influence of Th1 versus Th2 immune bias on viral, pathological, and immunological dynamics in SARS-CoV-2 variant-infected human ACE2 knock-in mice,” include Erin Maule, Paolla B. A. Pinto, Chris Conner, Kristen Valentine, Dale O Cowley, Robyn Miller, Annie Elong Ngono, Linda Tran, Krithik Varghese, Rúbens Prince dos Santos Alves, Kathryn M. Hastie, and Erica Ollmann Saphire.
This research received backing from the National Institutes of Health (grant U19 AI142790-02S1 and R44 AI157900), the GHR Foundation, the Arvin Gottlieb Charitable Foundation, the Overton family, and an American Association of Immunologists Career Reentry Fellowship (FASB).
