| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
eLife, Vol 11 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
2050-084X |
| DOI: |
10.7554/eLife.74623 |
| Popis: |
Despite tremendous progress in the understanding of COVID-19, mechanistic insight into immunological, disease-driving factors remains limited. We generated maVie16, a mouse-adapted SARS-CoV-2, by serial passaging of a human isolate. In silico modeling revealed how only three Spike mutations of maVie16 enhanced interaction with murine ACE2. maVie16 induced profound pathology in BALB/c and C57BL/6 mice, and the resulting mouse COVID-19 (mCOVID-19) replicated critical aspects of human disease, including early lymphopenia, pulmonary immune cell infiltration, pneumonia, and specific adaptive immunity. Inhibition of the proinflammatory cytokines IFNγ and TNF substantially reduced immunopathology. Importantly, genetic ACE2-deficiency completely prevented mCOVID-19 development. Finally, inhalation therapy with recombinant ACE2 fully protected mice from mCOVID-19, revealing a novel and efficient treatment. Thus, we here present maVie16 as a new tool to model COVID-19 for the discovery of new therapies and show that disease severity is determined by cytokine-driven immunopathology and critically dependent on ACE2 in vivo. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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