ACE2 is the critical in vivo receptor for SARS-CoV-2 in a novel COVID-19 mouse model with TNF- and IFNγ-driven immunopathology
0301 basic medicine
QH301-705.5
Science
Immunology
Adaptive Immunity
Peptidyl-Dipeptidase A
Interferon-gamma
03 medical and health sciences
Immunology and Inflammation
maVie16
Animals
Immunologia
Biology (General)
recombinant soluble ace2
Mice, Inbred BALB C
mouse-adapted SARS-CoV-2
SARS-CoV-2
Q
R
COVID-19
COVID-19 mouse model
3. Good health
Mice, Inbred C57BL
Disease Models, Animal
cytokine storm
Spike Glycoprotein, Coronavirus
Medicine
COVID-19 therapy
Angiotensin-Converting Enzyme 2
DOI:
10.7554/elife.74623
Publication Date:
2022-01-13T13:00:31Z
AUTHORS (24)
ABSTRACT
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.
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CITATIONS (54)
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