A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures

被引:364
作者
Dinnon, Kenneth H., III [1 ]
Leist, Sarah R. [2 ]
Schafer, Alexandra [2 ]
Edwards, Caitlin E. [2 ]
Martinez, David R. [2 ]
Montgomery, Stephanie A. [3 ]
West, Ande [2 ]
Yount, Boyd L., Jr. [2 ]
Hou, Yixuan J. [2 ]
Adams, Lily E. [1 ]
Gully, Kendra L. [2 ]
Brown, Ariane J. [2 ]
Huang, Emily [2 ]
Bryant, Matthew D. [4 ]
Choong, Ingrid C. [4 ]
Glenn, Jeffrey S. [5 ,6 ]
Gralinski, Lisa E. [2 ]
Sheahan, Timothy P. [2 ]
Baric, Ralph S. [1 ,2 ,7 ]
机构
[1] Univ North Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27515 USA
[2] Univ North Carolina, Dept Epidemiol, Chapel Hill, NC 27515 USA
[3] Univ North Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27515 USA
[4] Eiger BioPharmaceut, Palo Alto, CA USA
[5] Stanford Univ, Dept Med & Microbiol & Immunobiol, Stanford, CA 94305 USA
[6] Palo Alto Vet Adm, Palo Alto, CA USA
[7] Univ North Carolina, Rapidly Emerging Antiviral Drug Discovery Initiat, Chapel Hill, NC 27515 USA
基金
美国国家卫生研究院;
关键词
ACUTE RESPIRATORY SYNDROME; LENGTH INFECTIOUS CDNA; RANDOMIZED PHASE 2B; REVERSE GENETICS; SARS; LAMBDA; IFN; PROTECTION; ESCAPE; MICE;
D O I
10.1038/s41586-020-2708-8
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
A model in mouse using a species-adapted virus recapitulates features of SARS-CoV-2 infection and age-related disease pathogenesis in humans, and provides a model system for rapid evaluation of medical countermeasures against coronavirus disease 2019 (COVID-19). Coronaviruses are prone to transmission to new host species, as recently demonstrated by the spread to humans of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic(1). Small animal models that recapitulate SARS-CoV-2 disease are needed urgently for rapid evaluation of medical countermeasures(2,3). SARS-CoV-2 cannot infect wild-type laboratory mice owing to inefficient interactions between the viral spike protein and the mouse orthologue of the human receptor, angiotensin-converting enzyme 2 (ACE2)(4). Here we used reverse genetics(5)to remodel the interaction between SARS-CoV-2 spike protein and mouse ACE2 and designed mouse-adapted SARS-CoV-2 (SARS-CoV-2 MA), a recombinant virus that can use mouse ACE2 for entry into cells. SARS-CoV-2 MA was able to replicate in the upper and lower airways of both young adult and aged BALB/c mice. SARS-CoV-2 MA caused more severe disease in aged mice, and exhibited more clinically relevant phenotypes than those seen inHfh4-ACE2transgenic mice, which express human ACE2 under the control of theHfh4(also known asFoxj1) promoter. We demonstrate the utility of this model using vaccine-challenge studies in immune-competent mice with native expression of mouse ACE2. Finally, we show that the clinical candidate interferon-lambda 1a (IFN-lambda 1a) potently inhibits SARS-CoV-2 replication in primary human airway epithelial cells in vitro-both prophylactic and therapeutic administration of IFN-lambda 1a diminished SARS-CoV-2 replication in mice. In summary, the mouse-adapted SARS-CoV-2 MA model demonstrates age-related disease pathogenesis and supports the clinical use of pegylated IFN-lambda 1a as a treatment for human COVID-19(6).
引用
收藏
页码:560 / +
页数:13
相关论文
共 47 条
[1]   Uncovering inherent cellular plasticity of multiciliated ependyma leading to ventricular wall transformation and hydrocephalus [J].
Abdi, Khadar ;
Lai, Chun-Hsiang ;
Paez-Gonzalez, Patricia ;
Lay, Mark ;
Pyun, Joon ;
Kuo, Chay T. .
NATURE COMMUNICATIONS, 2018, 9
[2]  
Agnihothram S, 2018, J VIROL, V92, DOI [10.1128/jvi.00027-18, 10.1128/JVI.00027-18]
[3]   COVID-19: lambda interferon against viral load and hyperinflammation [J].
Andreakos, Evangelos ;
Tsiodras, Sotirios .
EMBO MOLECULAR MEDICINE, 2020, 12 (06)
[4]   Presumed Asymptomatic Carrier Transmission of COVID-19 [J].
Bai, Yan ;
Yao, Lingsheng ;
Wei, Tao ;
Tian, Fei ;
Jin, Dong-Yan ;
Chen, Lijuan ;
Wang, Meiyun .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2020, 323 (14) :1406-1407
[5]   The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice [J].
Bao, Linlin ;
Deng, Wei ;
Huang, Baoying ;
Gao, Hong ;
Liu, Jiangning ;
Ren, Lili ;
Wei, Qiang ;
Yu, Pin ;
Xu, Yanfeng ;
Qi, Feifei ;
Qu, Yajin ;
Li, Fengdi ;
Lv, Qi ;
Wang, Wenling ;
Xue, Jing ;
Gong, Shuran ;
Liu, Mingya ;
Wang, Guanpeng ;
Wang, Shunyi ;
Song, Zhiqi ;
Zhao, Linna ;
Liu, Peipei ;
Zhao, Li ;
Ye, Fei ;
Wang, Huijuan ;
Zhou, Weimin ;
Zhu, Na ;
Zhen, Wei ;
Yu, Haisheng ;
Zhang, Xiaojuan ;
Guo, Li ;
Chen, Lan ;
Wang, Conghui ;
Wang, Ying ;
Wang, Xinming ;
Xiao, Yan ;
Sun, Qiangming ;
Liu, Hongqi ;
Zhu, Fanli ;
Ma, Chunxia ;
Yan, Lingmei ;
Yang, Mengli ;
Han, Jun ;
Xu, Wenbo ;
Tan, Wenjie ;
Peng, Xiaozhong ;
Jin, Qi ;
Wu, Guizhen ;
Qin, Chuan .
NATURE, 2020, 583 (7818) :830-+
[6]   Peginterferon lambda for the treatment of HBeAg-positive chronic hepatitis B: A randomized phase 2b study (LIRA-B) [J].
Chan, Henry L. Y. ;
Ahn, Sang Hoon ;
Chang, Ting-Tsung ;
Peng, Cheng-Yuan ;
Wong, David ;
Coffin, Carla S. ;
Lim, Seng Gee ;
Chen, Pei-Jer ;
Janssen, Harry L. A. ;
Marcellin, Patrick ;
Serfaty, Lawrence ;
Zeuzem, Stefan ;
Cohen, David ;
Critelli, Linda ;
Xu, Dong ;
Wind-Rotolo, Megan ;
Cooney, Elizabeth .
JOURNAL OF HEPATOLOGY, 2016, 64 (05) :1011-1019
[7]  
Corbett Kizzmekia S, 2020, bioRxiv, DOI [10.1038/s41586-020-2622-0, 10.1101/2020.06.11.145920]
[8]   IFN is a potent anti-influenza therapeutic without the inflammatory side effects of IFN treatment [J].
Davidson, Sophia ;
McCabe, Teresa M. ;
Crotta, Stefania ;
Gad, Hans Henrik ;
Hessel, Edith M. ;
Beinke, Soren ;
Hartmann, Rune ;
Wack, Andreas .
EMBO MOLECULAR MEDICINE, 2016, 8 (09) :1099-1112
[9]   SARS and MERS: recent insights into emerging coronaviruses [J].
de Wit, Emmie ;
van Doremalen, Neeltje ;
Falzarano, Darryl ;
Munster, Vincent J. .
NATURE REVIEWS MICROBIOLOGY, 2016, 14 (08) :523-534
[10]   Emerging concepts for the treatment of hepatitis delta [J].
Elazar, Menashe ;
Glenn, Jeffrey S. .
CURRENT OPINION IN VIROLOGY, 2017, 24 :55-59