Gawish, RiemAgerer, BenediktEndler, LukasCapraz, TümayPerthold, Jan W.Cikes, DomagojKoglgruber, RubinaHagelkrüys, AstridMontserrat Pulido, NúriaMirazimi, AliBoon, LouisStarkl, PhilippStockinger, HannesBergthaler, AndreasOostenbrink, ChrisPenninger, Josef M.Knapp, SylviaPimenov, LisabethHladik, AnastasiyaLakovits, KarinOberndorfer, FelicitasCronin, Shane J. F.Ohradanova-Repic, AnnaWirnsberger, Gerald2022-04-192022-04-192022-01-132050-084Xhttps://hdl.handle.net/2445/185033Despite 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.34 p.application/pdfengcc by (c) Gawish, Riem et al, 2022http://creativecommons.org/licenses/by/3.0/es/COVID-19ImmunologiaCOVID-19Immunologyinfo:eu-repo/semantics/article2022-04-14info:eu-repo/semantics/openAccess654510435023830