ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF- and IFNγ-driven immunopathology

• DOI: 10.7554/elife.74623
• Publication Date: 2022-01-13T13:00:31Z
• Authors: Riem Gawish; Philipp Starkl; Lisabeth Pimenov; Anastasiya Hladik; Karin Lakovits; Felicitas Oberndo...; Shane JF Cronin; Anna Ohradanova-R...; 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
• Keywords: Proinflammatory cytokine; Cytokine Storm

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 human isolate. In silico modeling revealed how only three Spike mutations maVie16 enhanced interaction with murine ACE2. induced profound pathology BALB/c and C57BL/6 mice, resulting mouse COVID-19 (mCOVID-19) replicated critical aspects disease, including early lymphopenia, pulmonary immune cell infiltration, pneumonia, specific adaptive immunity. Inhibition proinflammatory cytokines IFNγ TNF substantially reduced immunopathology. Importantly, genetic ACE2-deficiency completely prevented mCOVID-19 development. Finally, inhalation therapy recombinant ACE2 fully protected mice from mCOVID-19, revealing novel efficient treatment. Thus, we here present as new tool to model for discovery therapies show that disease severity is determined cytokine-driven immunopathology critically dependent on vivo.