A Mouse Model of SARS-CoV-2 Infection and Pathogenesis

• Published in: Cell host & microbe Vol. 28; no. 1; pp. 124 - 133.e4
• Main Authors: Sun, Shi-Hui, Chen, Qi, Gu, Hong-Jing, Yang, Guan, Wang, Yan-Xiao, Huang, Xing-Yao, Liu, Su-Su, Zhang, Na-Na, Li, Xiao-Feng, Xiong, Rui, Guo, Yan, Deng, Yong-Qiang, Huang, Wei-Jin, Liu, Quan, Liu, Quan-Ming, Shen, Yue-Lei, Zhou, Yong, Yang, Xiao, Zhao, Tong-Yan, Fan, Chang-Fa, Zhou, Yu-Sen, Qin, Cheng-Feng, Wang, You-Chun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08-07-2020
• Subjects: Aging; Angiotensin-Converting Enzyme 2; angiotensin-converting enzyme II; Animals; Betacoronavirus - physiology; Brain - virology; Coronavirus Infections - pathology; Coronavirus Infections - virology; COVID-19; CRISPR-Cas Systems; Cytokines - blood; Disease Models, Animal; Gene Knock-In Techniques; hACE2-KI/NIFDC; Lung - pathology; Lung - virology; Lung Diseases, Interstitial - pathology; Mice, Inbred C57BL; mouse model; Nose - virology; Pandemics; pathogenesis; Peptidyl-Dipeptidase A - genetics; Peptidyl-Dipeptidase A - metabolism; Pneumonia, Viral - pathology; Pneumonia, Viral - virology; RNA, Viral - analysis; SARS-CoV-2; Stomach - virology; Trachea - virology; Viral Load; Virus Replication; pathogenesis; SARS-CoV-2; mouse model; angiotensin-converting enzyme II; hACE2-KI/NIFDC
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2020.05.020

Since December 2019, a novel coronavirus SARS-CoV-2 has emerged and rapidly spread throughout the world, resulting in a global public health emergency. The lack of vaccine and antivirals has brought an urgent need for an animal model. Human angiotensin-converting enzyme II (ACE2) has been identified as a functional receptor for SARS-CoV-2. In this study, we generated a mouse model expressing human ACE2 (hACE2) by using CRISPR/Cas9 knockin technology. In comparison with wild-type C57BL/6 mice, both young and aged hACE2 mice sustained high viral loads in lung, trachea, and brain upon intranasal infection. Although fatalities were not observed, interstitial pneumonia and elevated cytokines were seen in SARS-CoV-2 infected-aged hACE2 mice. Interestingly, intragastric inoculation of SARS-CoV-2 was seen to cause productive infection and lead to pulmonary pathological changes in hACE2 mice. Overall, this animal model described here provides a useful tool for studying SARS-CoV-2 transmission and pathogenesis and evaluating COVID-19 vaccines and therapeutics.
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•Human ACE2 knockin mice were generated by using CRISPR/Cas9 technology•SARS-CoV-2 leads to robust replication in lung, trachea, and brain•SARS-CoV-2 causes interstitial pneumonia and elevated cytokine in aged hACE2 mice•High dose of SARS-CoV-2 can establish infection via intragastric route in hACE2 mice
The COVID-19 pandemic has brought an urgent need for small animal models. Here, Sun et al. established an ACE2 humanized mouse by CRISPR/Cas9 knockin technology. These hACE2 mice are susceptible to SARS-CoV-2 infection upon intranasal inoculation, and the resulting pulmonary infection and pathological changes resemble those observed in COVID-19 patients.