What Are COVID-19 Humanized Mice and How Are They Used?

Animal models are a component of biomedical research, offering insights into disease function and treatment development. For a virus like SARS-CoV-2, standard laboratory animals are often unsuitable due to its specific interaction with human cells. This is where specialized models, known as humanized mice, are used. The development and application of these models have accelerated our understanding of COVID-19.

Defining Humanized Mice in Disease Research

A “humanized mouse” is a laboratory mouse that carries functioning human biological components, such as genes, cells, or tissues. The purpose of creating such a model is to study processes that are unique to human biology or disease within a living, controllable system. Standard lab mice cannot replicate many human-specific conditions, especially those involving the immune system or pathogens that only infect human cells.

The process of creating these mice often begins with a mouse that has a compromised immune system, preventing it from rejecting foreign human elements. Scientists can then introduce human hematopoietic stem cells, which develop into various human immune cells. In other cases, researchers might engraft small pieces of human tissue, such as lung tissue, allowing for direct study of how a pathogen or drug affects these specific tissues.

This approach has been used in other fields of medical research long before the COVID-19 pandemic. For example, humanized mice have been used to study the human immunodeficiency virus (HIV), as the virus does not naturally infect standard mice. In oncology, humanized mice implanted with human tumors are used to test the efficacy of new cancer therapies.

Engineering Mice for SARS-CoV-2 Susceptibility

The primary reason standard laboratory mice are not naturally susceptible to SARS-CoV-2 is because of a protein called angiotensin-converting enzyme 2 (ACE2). In humans, this protein acts as the main receptor that the virus’s spike protein uses to enter and infect cells. The mouse version of the ACE2 protein has a different structure and does not bind effectively with the viral spike protein. To overcome this, scientists engineered mice to express the human version of the ACE2 receptor (hACE2).

There are several methods to achieve this:

• Creating transgenic mice by inserting the human ACE2 gene directly into the mouse’s genome. This ensures the mouse’s cells produce the human protein, making them susceptible to infection.
• Using a harmless viral vector, such as an adenovirus, to deliver the hACE2 gene into the cells of an adult mouse. This method is faster than breeding transgenic mice.
• Engineering immunodeficient mice that are first engrafted with human stem cells to build a human immune system and then made to express hACE2 in their lung tissues.

These complex models allow for studying both the viral infection and the human immune response to it simultaneously.

Key Discoveries from COVID-19 Humanized Mouse Models

The use of hACE2 mouse models has provided insights into how SARS-CoV-2 causes disease. By infecting these mice, scientists have been able to map the virus’s progression. Studies showed the virus primarily targets the lungs, consistent with the most severe symptoms seen in humans. Pathological analysis of tissues from infected mice revealed lung damage similar to that in human COVID-19 cases, providing a reliable platform for study.

These models have also been instrumental in understanding the wide spectrum of disease severity. Some models survived infection and displayed symptoms similar to a mild case of COVID-19, creating an opportunity to study non-lethal disease and the immune responses that lead to recovery. By crossbreeding these hACE2 mice with other lines that model conditions like diabetes, researchers can explore why individuals with these comorbidities experience more severe outcomes.

These mice have also helped clarify the role of different components of the immune response. Scientists have created several mouse lines with different genetic backgrounds to examine how host genetics influence the immune reaction to various SARS-CoV-2 variants. Observing the immune response in these mice helps explain why some individuals mount an effective defense while others suffer from a dysregulated immune reaction.

Contribution to Therapeutic and Vaccine Evaluation

Humanized mouse models are also used for the preclinical evaluation of new treatments and vaccines for COVID-19. Before human trials, a potential drug or vaccine must show evidence of safety and efficacy in an animal model. The hACE2 mice provide a platform where researchers can test whether a candidate therapy can reduce viral load or protect against infection.

These models are used to assess the effectiveness of antiviral drugs designed to block SARS-CoV-2 replication. Researchers can treat infected hACE2 mice with a drug and measure the amount of virus in their tissues compared to untreated mice. Monoclonal antibody therapies, which use lab-made antibodies to neutralize the virus, have also been tested in these models to confirm they can prevent or treat disease.

Vaccine development has also relied on these mouse models. Scientists can administer a candidate vaccine to hACE2 mice and then expose them to the live virus to see if the vaccine provides protection. Researchers analyze the mice’s immune response to the vaccine, measuring levels of neutralizing antibodies and the activation of T-cells. This process helps identify the most promising candidates to move forward into human clinical trials.