Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling

Severe acute respiratory syndrome–coronavirus 2 (SARS-Cov-2) has caused over 13,000,000 cases of coronavirus disease (COVID-19) with a significant fatality rate. Laboratory mice have been the stalwart of therapeutic and vaccine development; however, they do not support infection by SARS-CoV-2 due to...

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Published inThe Journal of experimental medicine Vol. 217; no. 12
Main Authors Israelow, Benjamin, Song, Eric, Mao, Tianyang, Lu, Peiwen, Meir, Amit, Liu, Feimei, Alfajaro, Mia Madel, Wei, Jin, Dong, Huiping, Homer, Robert J., Ring, Aaron, Wilen, Craig B., Iwasaki, Akiko
Format Journal Article
LanguageEnglish
Published United States Rockefeller University Press 07.12.2020
Subjects
Angiotensin-Converting Enzyme 2
Animals
Betacoronavirus - metabolism
Cell Line, Tumor
Coronavirus Infections - metabolism
Coronavirus Infections - pathology
Coronavirus Infections - virology
COVID-19
Dependovirus - genetics
Disease Models, Animal
Female
Humans
Infectious Disease and Host Defense
Inflammation - metabolism
Innate Immunity and Inflammation
Interferon Type I - metabolism
Lung - pathology
Lung - virology
Male
Mice - genetics
Mice, Inbred C57BL
Mice, Transgenic
Pandemics
Parvoviridae Infections - metabolism
Parvoviridae Infections - virology
Peptidyl-Dipeptidase A - genetics
Peptidyl-Dipeptidase A - metabolism
Pneumonia, Viral - metabolism
Pneumonia, Viral - pathology
Pneumonia, Viral - virology
SARS-CoV-2
Signal Transduction - genetics
Virus Replication - genetics
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Summary:Severe acute respiratory syndrome–coronavirus 2 (SARS-Cov-2) has caused over 13,000,000 cases of coronavirus disease (COVID-19) with a significant fatality rate. Laboratory mice have been the stalwart of therapeutic and vaccine development; however, they do not support infection by SARS-CoV-2 due to the virus’s inability to use the mouse orthologue of its human entry receptor angiotensin-converting enzyme 2 (hACE2). While hACE2 transgenic mice support infection and pathogenesis, these mice are currently limited in availability and are restricted to a single genetic background. Here we report the development of a mouse model of SARS-CoV-2 based on adeno-associated virus (AAV)–mediated expression of hACE2. These mice support viral replication and exhibit pathological findings found in COVID-19 patients. Moreover, we show that type I interferons do not control SARS-CoV-2 replication in vivo but are significant drivers of pathological responses. Thus, the AAV-hACE2 mouse model enables rapid deployment for in-depth analysis following robust SARS-CoV-2 infection with authentic patient-derived virus in mice of diverse genetic backgrounds.
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B. Israelow and E. Song contributed equally to this paper.
Disclosures: A. Ring reported a patent to novel binding partner that interacts with SARS-CoV2 spike N-terminal domain pending; reports, "Unrelated to the subject of the work, I have founded, co-founded, and/or hold equity in biotechnology companies including Simcha Therapeutics, Forty Seven Inc., and ALX Oncology. I have also consulted for Medicenna Therapeutics, a company that licensed patents I invented in immuno-oncology. None of these companies are in the SARS-CoV-2 space or work on infectious disease to my knowledge. Broadly related to the subject of this work, within the past year, I have purchased and disposed shares in Gilead Sciences and Vir Biotechnology, which are working on therapeutics in the coronavirus space. I currently hold no shares in either of those companies." No other disclosures were reported.
ISSN:0022-1007
1540-9538
1540-9538
DOI:10.1084/jem.20201241