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ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF-and IFN?-driven immunopathology 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 COVID-19 Immunologia COVID-19 Immunology 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. 2022-04-19T12:07:13Z 2022-04-19T12:07:13Z 2022-01-13 2022-04-14T05:25:51Z info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion 2050-084X https://hdl.handle.net/2445/185033 6545104 35023830 eng Reproducció del document publicat a: https://doi.org/10.7554/eLife.74623 Elife, 2022 https://doi.org/10.7554/eLife.74623 cc by (c) Gawish, Riem et al, 2022 http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess 34 p. application/pdf eLife Sciences Publications Limited Articles publicats en revistes (Institut de Bioenginyeria de Catalunya (IBEC))