Transgenic mouse model could recapitulate severe COVID-19 in humans

By Sally Robertson, B.Sc.Nov 26 2020

Researchers in the United States and Canada have described the potential for a transgenic mouse model to serve as an effective platform for the study of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe disease course in humans.

Study: SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function. Image Credit: NIAID

As recently reported in the journal Nature Immunology, the model shares many features of severe coronavirus disease 2019 (COVID-19) in people and could be useful for evaluating immunomodulatory and antiviral-based drugs.

“Although animal models have been evaluated for SARS-CoV-2 infection, none have fully recapitulated the lung disease phenotypes seen in humans who have been hospitalized,” says the team from Washington University School of Medicine and SCIREQ Scientific Respiratory Equipment in Montreal.

Now, the researchers have shown that the onset of severe clinical disease occurred in the transgenic mice just days after viral infection peaked and was associated with high levels of infiltrating immune cells and inflammatory mediators in the lung.

“This course is remarkably consistent with human disease in which rapid early viral replication is followed by inflammatory responses, which are believed to contribute to pathology, morbidity and mortality,” writes Emma Winkler (Washington University School of Medicine) and colleagues.

SARS-CoV-2 disease course is highly variable

The clinical manifestations of SARS-CoV-2 infection are highly variable, ranging from mild or even no symptoms to severe outcomes, including multi-organ failure and death.

To infect host cells, the virus uses a surface structure called the spike protein to bind and fuse with the human receptor angiotensin-converting enzyme 2 (hACE2).

This binding of hACE2 primarily directs the virus towards pneumocytes within the lung, where it can cause injury, inflammation and fatal respiratory distress.

“The development of countermeasures that reduce COVID-19 morbidity and mortality is a priority for the global research community, and animal models are essential for this effort,” said Winkler and colleagues.

However, no animal models have yet been developed that recapture the severe disease that occurs in humans.

Hamsters, ferrets and even non-human primates, for example, only develop mild-to-moderate disease and conventional mouse models do not support SARS-CoV-2 binding.

“Thus, additional animal models are needed to enable understanding of the biology of severe SARS-CoV-2 infection in the lung and evaluation of the efficacy of antiviral and immunomodulatory countermeasures,” write the researchers.

The K18-hACE2-transgenic mice model

One platform that has been shown to cause lethal SARS infection in animals is the K18-hACE2-transgenic mouse model, where successful hACE2 expression is driven by the epithelial cell cytokeratin-18 (K18) promoter.

The model was initially developed to study the pathogenesis of SARS-CoV-1 following the 2002 to 2003 SARS outbreak.

Now, Winkler and the team have evaluated hACE2-transgenic mice as a potential model of SARS-CoV-2 infection and subsequent severe COVID-19 disease.

What did the study find?

Following intranasal SARS-CoV-2 inoculation, the mice started to lose weight just 4 days post-infection and had succumbed to severe disease by day 7.

High levels of viral RNA and infectious virus were detected in the lungs as early as 2, 4 and 7 days following inoculation.

Pulmonary function declined just four days after viral titers peaked and was accompanied by infiltration of monocytes, neutrophils, and activated T cells in the lung, as well as high levels of pro-inflammatory cytokines and chemokines.

This combination of infection and inflammation led to the development of severe interstitial pneumonia characterized by collapsed alveolar spaces, compromised gaseous exchange and stiffening of the lung parenchyma.

An attractive small animal model for understanding severe COVID-19

This disease course is “remarkably consistent with human disease,” say the researchers, which makes the K18-hACE2 mouse an attractive small animal model for understanding the pathogenesis of severe COVID-19.

“Because of its severe disease and intense immune cell infiltration, the K18-hACE2 model of SARS-CoV-2 infection may facilitate evaluation of immunomodulatory and antiviral drugs against COVID-19 and our understanding of immune-mediated mechanisms of pathogenesis,” concludes the team.