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A novel experimental model of Covid-19

Scientists from IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University have developed an innovative animal model of SARS-CoV-2 infection, that will improve accuracy and predictivity of international scientific research on Covid-19.

The model, described today in Science Immunology, will allow researchers to study the transmission mechanisms of SARS-CoV-2, Covid-19 acute infection and long-term consequences, as well as to test the effectiveness of new antivirals and vaccines.

The research was coordinated by Matteo Iannacone, head of the Dynamics of Immune Responses research group and associate professor at Vita-Salute San Raffaele University in Milan, and Luca Guidotti, head of the Immunopathology research group, deputy scientific director of the IRCCS Ospedale San Raffaele and full professor at the same university.

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San Raffaele's P3 biosafety laboratory.

Covid-19 experimental models

Finding effective therapies and vaccines against SARS-CoV-2 infection would not be possible without animal models that help researchers replicate the clinical manifestations of Covid-19 we observe in humans. Moreover, better understanding SARS-CoV-2 and its interaction with the immune system in-vivo can prepare us for possible future zoonosis of new coronaviruses belonging to the same family (which also includes MERS and SARS viruses).

The experimental model used today in laboratories around the world – the one that allowed for the test of the first antivirals and vaccines – was in fact developed between 2003 and 2005, following the SARS outbreak, by a group of researchers from the University of Iowa. It is a genetically modified mouse that expresses the same receptor (called hACE2) present in humans respiratory tract cells and to which the Spike protein binds efficiently. The mouse is then infected, under deep anesthesia, using a liquid solution containing the novel coronavirus.

“This model, unfortunately, replicates the disease observed in humans quite poorly. Compared to us, mice show fewer respiratory symptoms and a robust infection of the nervous system, making the study of the disease, its long-term impact and drug efficacy tests much more difficult and slower" explains Matteo Iannacone.

The new model developed at San Raffaele

That’s why researchers led by professors Iannacone and Guidotti worked on a new experimental model, based on a different infection technique, that better resembles the natural route of contagion in humans: mice are exposed to an aerosol of viral particles in suspension, mimicking what happens when we enter a room with a high viral concentration and without knowing it, the virus enters our upper respiratory tract.

Using this new approach, the transgenic mice exhibit all the characteristics known to the human disease, such as the inflammation and obstruction of the respiratory tract and the loss of smell. In addition to allowing a better understanding of the pathophysiological mechanisms of Covid-19, the model will also help us to better understand how temperature, humidity and concentration of viral particles influence the probability of contagion and the severity of the illness.

"The development of new and increasingly effective and safe therapies against viral infections such as Covid-19 depends on our ability to build accurate experimental models, as close as possible to what actually happens in patients" says Luca Guidotti, head of the in-vivo research on Covid-19 at Ospedale San Raffaele. "As the recent successes in the field of Hepatitis B show, it is thanks to cutting-edge technological platforms, high biosafety level laboratories and multidisciplinary skills that an institute like ours can make a difference in the fight against viruses."

This work was conducted within the only P3 biosafety laboratory in Italy for the in-vivo study of highly dangerous viruses through advanced imaging and gene sequencing technologies. Between 2020 and 2021 the laboratory was partially converted to the study of SARS-CoV-2 and Covid-19 thanks to the support of Same Deutz Fahr Group and Prossimo Mio Foundation.