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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/185033
ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF-and IFN?-driven immunopathology
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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 cyto-kines IFN? 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. © Gawish et al.
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GAWISH, Riem, AGERER, Benedikt, ENDLER, Lukas, CAPRAZ, Tümay, PERTHOLD, Jan w., CIKES, Domagoj, KOGLGRUBER, Rubina, HAGELKRÜYS, Astrid, MONTSERRAT PULIDO, Núria, MIRAZIMI, Ali, BOON, Louis, STARKL, Philipp, STOCKINGER, Hannes, BERGTHALER, Andreas, OOSTENBRINK, Chris, PENNINGER, Josef m., KNAPP, Sylvia, PIMENOV, Lisabeth, HLADIK, Anastasiya, LAKOVITS, Karin, OBERNDORFER, Felicitas, CRONIN, Shane j. f., OHRADANOVA-REPIC, Anna, WIRNSBERGER, Gerald. ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF-and IFN?-driven immunopathology. _Elife_. 2022. [consulta: 23 de gener de 2026]. ISSN: 2050-084X. [Disponible a: https://hdl.handle.net/2445/185033]