humanized mouse
Research Models
Regina Kelder

Humanized Mice Join Other Animal Models in the COVID-19 Fight

Unique new mouse models will help us study the immune system and severe inflammatory responses in COVID-19 patients

When the novel SARS-CoV-2 virus emerged 12 months ago, dozens of groups raced to develop animal models to help find effective treatments and vaccines for COVID-19, and to clarify precisely how the virus immediately caused disease. This fast-paced global effort produced several huge wins.

Through the cooperative efforts of labs around the world, we have several commercially available vaccines, with more on the way later this year. We also have two novel antibody treatments that work extremely well on critically ill COVID-19 patients. We also have a fairly good idea of what happens after a person becomes infected SARS-CoV-2. We have learned, for instance, that COVID-19 is not exclusively a respiratory illness but can impact multiple organs.

Much of this progress would not have been possible without the help of animal models. Syrian hamsters became important players early on because these tiny creatures are susceptible to SARS-CoV-2 and therefore express many of the same COVID-19 symptoms as humans. High levels of SARS-CoV-2 were found in the hamsters’ lungs and intestines in tissues studded with the virus’ target, a protein receptor called angiotensin-converting enzyme 2 (ACE2), and there have been multiple studies since the pandemic began validating the usefulness of the Syrian hamster model.

Ferrets, a popular choice in influenza research, do not develop COVID-19 symptoms, but they do appear to mimic transmission of the virus, making them valuable in certain COVID-19 studies. New Zealand rabbits and large animal species have been valuable in the studies of vaccines and therapeutics.

But there is still much we don’t know about why some patients get sick, have long lasting effects and some die of COVID-19, while others develop only mild symptoms. A humanized mouse model of COVID-19 could help provide some answers.

Basic rodent models have long been the workhorse of research, but in the case of COVID-19 they aren’t a practical choice because they resist infection and their ACE2 receptor is too dissimilar to ours. You could re-engineer them or you could humanize them. A study led by the James Graham Brown Cancer Center in Louisville and published last year in Stem Cells Rev Rep found human ACE2 is expressed in hematopoetic and endothelial cells and that ACE2 was expressed on the surface of murine bone marrow-derived very small embryonic-like stem cells and hematopoietic stem cells, though it is also known that murine cells are not infected by SARS-CoV-2.

To get around this obstacle, scientists have built develop a triple immunodeficient humanized mouse model that engrafts CD34+ cord blood and supports hematopoiesis of human immune cell types known to express ACE2. Charles River is assessing the susceptibility of the HuNCG model to SARS-CoV-2 infection. The HuNCG model as a starting point will hopefully provide a vehicle for labs around the world to study how the immune system and inflammatory response of some COVID-19 patients inflicts devastating damage on a significant subset of COVID-19 infected patients. Having a model like this could lead to a better understanding of SARS-CoV-2 infection, anti-virus therapies and to the development of drugs for the treatment and prevention of the disease.

“The unique aspect of the NCG is that we can bring human immune cells with a mouse’s susceptibility to a human virus,” said Steve Festin, PhD, Director of Scientific and Commercial Development, RMS Services, at Charles River.

Humanizing the murine immune system, which involves taking human tissue and engrafting it into immunodeficient mouse models, is not a new technology. Experiments in transplanting human tissue into mice began around three decades ago, and about 14 years ago researchers finally succeeded in creating mice that could successfully harbor human immune cells and be infected with human viruses that the mice shrug off.

Since then, mice have been used to study HIV and certain cancers and have been an important tool in studying the translatability of immuno-oncology drugs. Humanized models are broadly applicable to cancer cell lines common in the study of cancer oncology as well as patient-derived xenograft models (PDX models) where tissue or cells from a cancer patient are implanted into a humanized mouse. Given the nature of COVID-19, it’s not surprising that there is now a humanized mouse model for COVID-19, too.

Festin said it is still very early days for the HuNCG as a model for COVID-19 and more data will need to be collected to demonstrate its utility in COVID research. But he is optimistic about its future. “I think it is going to be most useful in studying the mechanisms of different immune cells or T cell responses to the virus.”

Log on to Charles River’s humanized mouse portfolio and learn how these models and other humanized models can better support researchers focused on predicting human responses to new therapeutics in clinical development.