Animal models are tools in biomedical research, offering a way to study how diseases affect a living organism and test new treatments. The laboratory mouse has been a principal model due to its genetic similarity to humans, short lifespan, and ease of handling. When SARS-CoV-2 emerged, scientists turned to these animals to understand the virus but encountered a biological barrier that required significant innovation to overcome.
The Challenge of Using Mice for COVID-19 Research
The primary obstacle in using standard laboratory mice for COVID-19 research lies at the molecular level. The virus is covered in spike proteins, which act like a key for a specific lock on a host’s cells called angiotensin-converting enzyme 2, or ACE2. Human cells, particularly in the respiratory tract, are covered in ACE2 receptors, providing many points of entry for the virus.
This mechanism is where the problem with mice arises. Although mice also have ACE2 receptors, the protein’s structure is different from the human version. Due to significant amino acid sequence variations in the part of the receptor that the virus binds to, the SARS-CoV-2 spike protein cannot effectively attach to the mouse ACE2 receptor. This molecular incompatibility means the virus’s “key” does not fit the mouse’s “lock.”
As a result, typical laboratory mice are naturally resistant to infection from the initial strains of SARS-CoV-2. When exposed, the virus fails to gain a foothold, cannot replicate efficiently, and does not cause disease. This resistance rendered existing mouse strains unsuitable for studying the virus’s behavior or for testing potential vaccines and therapies.
Creating Susceptible Mouse Models
To overcome the natural resistance of mice to SARS-CoV-2, scientists developed two primary strategies to create models that could be infected. The first method was genetic engineering. Researchers created transgenic mice by inserting the gene for the human ACE2 (hACE2) receptor into the mouse’s genome. This process installs the correct “lock” onto the surface of the mouse’s cells, allowing the virus to enter and replicate.
One prominent example is the K18-hACE2 mouse. In this model, the hACE2 gene is linked to a promoter that directs the expression of the hACE2 receptor to epithelial cells, including those lining the airways. This ensures the virus can infect the respiratory tract, mimicking a key aspect of human infection. These transgenic mice become susceptible to the virus and develop symptoms, making them a viable platform for research.
A second approach involved adapting the virus itself through serial passaging. This method involves repeatedly exposing mice to the virus by transferring lung tissue from an infected mouse to a new one. With each “passage,” the virus is under evolutionary pressure to mutate in ways that make it better at infecting mouse cells.
Through this process, strains of SARS-CoV-2 emerged with mutations in their spike protein that allowed it to bind more effectively to the mouse ACE2 receptor. The result was a mouse-adapted virus capable of infecting standard laboratory mice, which are less expensive and more widely available than transgenic models.
Key Discoveries from Mouse Studies
The development of susceptible mouse models led to important findings about how COVID-19 progresses. Using hACE2 mice, scientists observed the direct effects of viral replication in the lungs. Studies showed that infection led to interstitial pneumonia, with inflammation and tissue thickening similar to the lung damage seen in severe human cases. These models were helpful in studying the aggressive immune response, often called a cytokine storm.
Researchers observed that infected K18-hACE2 mice exhibited an upregulation of pro-inflammatory cytokines in the lungs, along with an infiltration of immune cells. This helped confirm the mechanisms behind the severe respiratory distress associated with the disease. Furthermore, some models showed that the virus could travel to other organs, including the brain, which helped researchers investigate neurological symptoms reported by some COVID-19 patients.
These mouse models also served as platforms for the preclinical testing of vaccines and antiviral treatments. Candidate vaccines were tested in mice to confirm they could produce a protective immune response. Vaccinated animals had significantly lower viral loads in their lungs and were protected from severe lung damage. Antiviral drugs were also screened to assess their ability to reduce viral replication and lessen disease severity.
Limitations of Mouse Models
While mouse models have been useful, they do not perfectly replicate every aspect of human COVID-19. A significant limitation is that the disease in mice does not always capture the full spectrum of symptoms or severity. For instance, while hACE2 mice can develop severe lung disease, they often do not exhibit the range of mild or moderate symptoms that characterize the majority of human infections.
There are also foundational differences in the mouse immune system compared to that of humans. These differences can influence how the disease progresses and how the animal responds to treatments or vaccines. The types and proportions of immune cells, as well as the specific inflammatory pathways, can vary, meaning a response seen in a mouse might not directly translate to a human.
Because of these limitations, a single animal model is insufficient to understand a complex disease like COVID-19. Findings from mice are often complemented by research using other animal models. Golden Syrian hamsters, for example, reliably develop respiratory disease that more closely mirrors moderate human illness. Non-human primates, such as rhesus macaques, have immune systems more similar to humans and provide another layer of data for studying vaccine efficacy before human trials.