Whether it’s about the mechanisms of a disease or the development of effective and safe vaccines, drugs and therapies, adequate disease models also play an important role in research into COVID-19. In search of ever better tools, a research group led by LSI Director Dr. Josef Penninger, and Dr. Sylvia Knapp at MedUni Vienna has developed a new Covid-19 mouse model presented in a study recently published in the specialist journal “eLife”.
Because the immune systems of mice and humans are similar in many ways, mouse models are particularly important in research into COVID-19. Yet mice could not – or could only with difficulty be infected with SARS-CoV-2 – due to a genetic peculiarity. The reason: The entry receptor ACE2, to which the coronavirus latches with its typical spike proteins, is designed differently in animals than in humans.
Portal of entry for coronavirus
ACE2 (angiotensin converting enzyme 2) is located in the outer membrane of the body’s cells, where it is involved in the regulation of blood pressure and thus has a protective function for the cardiovascular system. For SARS-CoV-2, ACE2 is the gateway the virus uses to enter the cells in order to infect them. Whether and how efficiently the virus can infect a species depends on how well it can bind to ACE2 with its spike surface protein. Due to genetic differences, ACE2 has a different structure in mice than in humans, which is why mice are more resistant to infection with SARS-CoV-2.
Infection becomes possible via spike mutations
An interdisciplinary research team led by Sylvia Knapp, Head of the Infection Biology Research Laboratory at MedUni Vienna’s Department of Medicine, collaborated with Dr. Penninger’s lab based at the Institute for Molecular Biotechnology in Vienna, as well as Chris Oostenbrink (BOKU), Andreas Bergthaler and Hannes Stockinger (MedUni Vienna) to develop a new mouse model for research into Covid-19. This is based on viral mutations of SARS-CoV-2, which has caused the virus to change its spike proteins in such a way that it can bind well to the ACE2 receptor in mice. Only three mutations in the viral spike protein were necessary for efficient infection and replication in mice. As a result, the animals can become infected and also develop corresponding symptoms of the disease.
In the study, the researchers showed that administration of synthetic ACE2 as an inhalant can protect against infections with SARS-CoV2. Inflammation triggered by interferon-γ and tumor necrosis factor TNF, both of which are highly implicated in COVID-19, can be significantly alleviated by blocking disease progression.
Advancing COVID-19 research
First authors Riem Gawish and Philipp Starkl from MedUni’s Department of Internal Medicine I, say this new mouse model is a valuable tool for advancing research into the mechanisms of COVID-19 and the development of vaccines, drugs and therapies, emphasize. In contrast to existing COVID-19 mouse models, this new tool can be used in common laboratory mouse lines without further manipulation, whereby both mild and severe disease courses can be modeled for research purposes, depending on the virus dosage.
ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF- and IFNγ-driven immunopathology
Riem Gawish, Philipp Starkl, Lisabeth Pimenov, Anastasiya Hladik, Karin Lakovits, Felicitas Oberndorfer, Shane JF Cronin , Anna Ohradanova-Repic, Gerald Wirnsberger, Benedikt Agerer, Lukas Endler, Tümay Capraz, Jan W Perthold, Domagoj Cikes, Rubina Koglgruber, Astrid Hagelkruys, Nuria Montserrat, Ali Mirazimi, Louis Boon, Hannes Stockinger, Andreas Bergthaler, Chris Oostenbrink, Josef M Penninger, Sylvia Knapp
doi: 10.7554/eLife.74623
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