Mouse model of SARS-CoV-2 reveals inflammatory role of type I interferon signaling
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Abstract
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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In a murine model of SARS-CoV-2 infection, type I IFNs do not control SARS-CoV-2 replication in vivo but are significant drivers of pathologic responses.
“The dynamics of type I IFNs in severe patients is in line with findings in a murine model of SARS-CoV-2 infection illustrating that type I IFNs do not control SARS-CoV-2 replication in vivo but are significant drivers of pathologic responses (Israelow et al., 2020).”
From COVID-19 and the human innate immune system (2021) · cites this paper as Israelow et al., 2020
The mouse model of mild SARS-CoV-2 infection used is limited to the respiratory system and clears within 1 week.
“To test the effects of mild COVID, we used a mouse model of mild SARS-CoV-2 infection limited to the respiratory system that clears within 1 week (Israelow et al., 2020; Song et al., 2021).”
From Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation (2022) · cites this paper as Israelow et al., 2020
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Cites
A novel coronavirus from patients with pneumonia in China, 2019
Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., Zhao, X., Huang, B., Shi, W., Lu, R., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2001017 · Cited by 28,244 · see citing works
Hoffmann, M., Kleine-Weber, H., Schroeder, S., Krüger, N., Herrler, T., Erichsen, S., Schiergens, T. S., Herrler, G., Wu, N.-H., Nitsche, A., et al. (2020) · Cell · doi:10.1016/j.cell.2020.02.052 · Cited by 20,286 · see citing works
Wang, D., Hu, B., Hu, C., Zhu, F., Liu, X., Zhang, J., Wang, B., Xiang, H., Cheng, Z., Xiong, Y., et al. (2020) · JAMA · doi:10.1001/jama.2020.1585 · Cited by 20,148 · see citing works
La certeza de lo impredecible: Cultura Educación y Sociedad en tiempos de COVID19
Martínez González, M. (2020) · DSPACE System - Metalibrary (University of the Coast) · Cited by 18,463 · see citing works
An interactive web-based dashboard to track COVID-19 in real time
Dong, E., Du, H., & Gardner, L. (2020) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(20)30120-1 · Cited by 10,048 · see citing works
Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19
Blanco-Melo, D., Nilsson-Payant, B. E., Liu, W.-C., Uhl, S., Hoagland, D., Møller, R., Jordan, T. X., Oishi, K., Panis, M., Sachs, D., et al. (2020) · Cell · doi:10.1016/j.cell.2020.04.026 · Cited by 4,222 · see citing works
Letko, M., Marzi, A., & Munster, V. (2020) · Nature Microbiology · doi:10.1038/s41564-020-0688-y · Cited by 3,109 · see citing works
Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19
Liao, M., Liu, Y., Yuan, J., Wen, Y., Xu, G., Zhao, J., Cheng, L., Li, J., Wang, X., Wang, F., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0901-9 · Cited by 2,614 · see citing works
Regulation of Adaptive Immunity by the Innate Immune System
Iwasaki, A., & Medzhitov, R. M. (2010) · Science · doi:10.1126/science.1183021 · Cited by 2,139 · see citing works
Self-citationA serological assay to detect SARS-CoV-2 seroconversion in humans
Amanat, F., Stadlbauer, D., Strohmeier, S., Nguyen, T. H. O., Chromikova, V., McMahon, M., Jiang, K., Arunkumar, G. A., Jurczyszak, D., Polanco, J., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0913-5 · Cited by 1,769 · see citing works
Channappanavar, R., Fehr, A. R., Vijay, R., Mack, M., Zhao, J., Meyerholz, D. K., & Perlman, S. M. (2016) · Cell Host & Microbe · doi:10.1016/j.chom.2016.01.007 · Cited by 1,400 · see citing works
Type I Inteferon Gene Induction by the Interferon Regulatory Factor Family of Transcription Factors
Honda, K., Takaoka, A., & Taniguchi, T. (2006) · Immunity · doi:10.1016/j.immuni.2006.08.009 · Cited by 1,386 · see citing works
Pathogenesis and transmission of SARS-CoV-2 in golden hamsters
Sia, S. F., Yan, L.-M., Chin, A. W. H., Fung, K., Choy, K.-T., Wong, A. Y. L., Kaewpreedee, P., Perera, R. A. P. M., Poon, L. L. M., Nicholls, J. M., et al. (2020) · Nature · doi:10.1038/s41586-020-2342-5 · Cited by 1,303 · see citing works
The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice
Bao, L., Deng, W., Huang, B., Gao, H., Liu, J., Ren, L., Wei, Q., Yu, P., Xu, Y., Qi, F., et al. (2020) · Nature · doi:10.1038/s41586-020-2312-y · Cited by 1,126 · see citing works
Heightened Innate Immune Responses in the Respiratory Tract of COVID-19 Patients
Zhou, Z. L., Ren, L., Zhang, L., Zhong, J., Xiao, Y., Jia, Z., Guo, L., Yang, J., Wang, C., Jiang, S., et al. (2020) · Cell Host & Microbe · doi:10.1016/j.chom.2020.04.017 · Cited by 963 · see citing works
Type I and Type III Interferons – Induction, Signaling, Evasion, and Application to Combat COVID-19
Park, A., & Iwasaki, A. (2020) · Cell Host & Microbe · doi:10.1016/j.chom.2020.05.008 · Cited by 909 · see citing works
Self-citationComparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate model
Rockx, B., Kuiken, T., Herfst, S., Bestebroer, T., Lamers, M. M., Oude Munnink, B. B., de Meulder, D., van Amerongen, G., van den Brand, J., Okba, N. M. A., et al. (2020) · Science · doi:10.1126/science.abb7314 · Cited by 901 · see citing works
Stadlbauer, D., Amanat, F., Chromikova, V., Jiang, K., Strohmeier, S., Arunkumar, G. A., Tan, J., Bhavsar, D., Capuano, C., Roubidoux, E. K., et al. (2020) · Current Protocols in Microbiology · doi:10.1002/cpmc.100 · Cited by 623 · see citing works
Pathogenesis of SARS-CoV-2 in Transgenic Mice Expressing Human Angiotensin-Converting Enzyme 2
Jiang, R.-D., Liu, M.-Q., Chen, Y., Shan, C., Zhou, Y.-W., Shen, X.-R., Li, Q., Zhang, L., Zhu, Y., Si, H.-R., et al. (2020) · Cell · doi:10.1016/j.cell.2020.05.027 · Cited by 541 · see citing works
A SARS-CoV-2 Infection Model in Mice Demonstrates Protection by Neutralizing Antibodies
Hassan, A. O., Case, J. B., Winkler, E. S., Thackray, L. B., Kafai, N. M., Bailey, A. L., McCune, B. T., Fox, J. M., Chen, R. E., Alsoussi, W. B., et al. (2020) · Cell · doi:10.1016/j.cell.2020.06.011 · Cited by 477 · see citing works
Galani, I. E., Triantafyllia, V., Eleminiadou, E.-E., Koltsida, O., Stavropoulos, A., Manioudaki, M., Thanos, D., Doyle, S. E., Kotenko, S. V., Thanopoulou, K., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.04.025 · Cited by 464 · see citing works
Rapid generation of a mouse model for Middle East respiratory syndrome
Zhao, J., Li, K., Wohlford-Lenane, C., Agnihothram, S., Fett, C., Zhao, J., Gale, M., Baric, R. S., Enjuanes, L., Gallagher, T., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1323279111 · Cited by 452 · see citing works
A Mouse-Adapted SARS-Coronavirus Causes Disease and Mortality in BALB/c Mice
Roberts, A., Deming, D., Paddock, C. D., Cheng, A., Yount, B. L., Vogel, L., Herman, B. D., Sheahan, T., Heise, M. T., Genrich, G. L., et al. (2007) · PLoS Pathogens · doi:10.1371/journal.ppat.0030005 · Cited by 447 · see citing works
Generation of a Broadly Useful Model for COVID-19 Pathogenesis, Vaccination, and Treatment
Sun, J., Zhuang, Z., Zheng, J. H., Li, K., Wong, R. L.-Y., Liu, D., Huang, J., He, J., Zhu, A., Zhao, J., et al. (2020) · Cell · doi:10.1016/j.cell.2020.06.010 · Cited by 434 · see citing works
Cameron, M. J., Ran, L., Xu, L., Danesh, A., Bermejo-Martin, J. F., Cameron, C. M., Muller, M. P., Gold, W. L., Richardson, S. E., Poutanen, S. M., et al. (2007) · Journal of Virology · doi:10.1128/jvi.00527-07 · Cited by 386 · see citing works
Pathogenic potential of interferon αβ in acute influenza infection
Davidson, S., Crotta, S., McCabe, T. M., & Wack, A. (2014) · Nature Communications · doi:10.1038/ncomms4864 · Cited by 370 · see citing works
The Roles of Type I Interferon in Bacterial Infection
Boxx, G. M., & Cheng, G. (2016) · Cell Host & Microbe · doi:10.1016/j.chom.2016.05.016 · Cited by 335 · see citing works
Metzemaekers, M., Vanheule, V., Janssens, R., Struyf, S., & Proost, P. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01970 · Cited by 325 · see citing works
Type I Interferons in Autoimmune Disease
Crow, M. K., Olferiev, M., & Kirou, K. A. (2018) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-020117-043952 · Cited by 297 · see citing works
Immunity to adenovirus and adeno-associated viral vectors: implications for gene therapy
Jooss, K. U., & Chirmule, N. B. (2003) · Gene Therapy · doi:10.1038/sj.gt.3302037 · Cited by 278 · see citing works
Boudewijns, R., Thibaut, H. J., Kaptein, S. J. F., Li, R., Vergote, V., Seldeslachts, L., Weyenbergh, J. V., Keyzer, C. D., Bervoets, L., Sharma, S., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19684-y · Cited by 275 · see citing works
Type I interferons instigate fetal demise after Zika virus infection
Yockey, L. J., Jurado, K. A., Arora, N., Millet, A., Rakib, T., Milano, K. M., Hastings, A. K., Fikrig, E., Kong, Y., Horváth, T. L., et al. (2018) · Science Immunology · doi:10.1126/sciimmunol.aao1680 · Cited by 253 · see citing works
Self-citationMx1 reveals innate pathways to antiviral resistance and lethal influenza disease
Pillai, P. S., Molony, R. D., Martinod, K., Dong, H., Pang, I. K., Tal, M. C., Solis, A. G., Bielecki, P., Mohanty, S., Trentalange, M. J., et al. (2016) · Science · doi:10.1126/science.aaf3926 · Cited by 241 · see citing works
Self-citationSeo, S., Kwon, H.-J., Ko, H.-J., Byun, Y.-H., Seong, B. L., Uematsu, S., Akira, S., & Kweon, M. (2011) · PLoS Pathogens · doi:10.1371/journal.ppat.1001304 · Cited by 211 · see citing works
Type I Interferons as Regulators of Lung Inflammation
Makris, S., Paulsen, M. T., & Johansson, C. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00259 · Cited by 159 · see citing works
The Evolution of Antiviral Defense Systems
tenOever, B. R. (2016) · Cell Host & Microbe · doi:10.1016/j.chom.2016.01.006 · Cited by 148 · see citing works
Day, C. W., Baric, R. S., Cai, S. X., Frieman, M. B., Kumaki, Y., Morrey, J. D., Smee, D. F., & Barnard, D. L. (2009) · Virology · doi:10.1016/j.virol.2009.09.023 · Cited by 139 · see citing works
Boudewijns, R., Thibaut, H. J., Kaptein, S. J. F., Li, R., Vergote, V., Seldeslachts, L., Keyzer, C. D., Bervoets, L., Sharma, S., Weyenbergh, J. V., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.04.23.056838 · Cited by 53 · see citing works
Coronavirus vaccines: five key questions as trials begin
Callaway, E. (2020) · Nature · doi:10.1038/d41586-020-00798-8 · Cited by 49 · see citing works
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Song, E., Zhang, C., Israelow, B., Lu-Culligan, A., Prado, A. V., Skriabine, S., Lu, P., Weizman, O.-E., Liu, F., Dai, Y., et al. (2020) · doi:10.1101/2020.06.25.169946 · Cited by 1,064 · see citing works
Self-citationWinkler, E. S., Bailey, A. L., Kafai, N. M., Nair, S., McCune, B. T., Yu, J., Fox, J. M., Chen, R. E., Earnest, J. T., Keeler, S. P., et al. (2020) · Nature Immunology · doi:10.1038/s41590-020-0778-2 · Cited by 901 · see citing works
Muñoz-Fontela, C., Dowling, W. E., Funnell, S. G. P., Gsell, P.-S., Riveros-Balta, A. X., Albrecht, R. A., Andersen, H., Baric, R. S., Carroll, M. W., Cavaleri, M., et al. (2020) · Nature · doi:10.1038/s41586-020-2787-6 · Cited by 798 · see citing works
COVID-19 and the human innate immune system
Schultze, J. L., & Aschenbrenner, A. C. (2021) · Cell · doi:10.1016/j.cell.2021.02.029 · Cited by 714 · see citing works
A Mouse-Adapted SARS-CoV-2 Induces Acute Lung Injury and Mortality in Standard Laboratory Mice
Leist, S. R., Dinnon, K. H., Schäfer, A., Tse, L. V., Okuda, K., Hou, Y. J., West, A., Edwards, C. E., Sanders, W., Fritch, E. J., et al. (2020) · Cell · doi:10.1016/j.cell.2020.09.050 · Cited by 613 · see citing works
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Domizio, J. D., Gulen, M. F., Saidoune, F., Thacker, V. V., Yatim, A., Sharma, K., Nass, T., Guenova, E., Schaller, M., Conrad, C., et al. (2022) · Nature · doi:10.1038/s41586-022-04421-w · Cited by 538 · see citing works
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- Authors
- Israelow, B., Song, E., Mao, T., Lu, P., Meir, A., Liu, F., Alfajaro, M. M., Wei, J., Dong, H., Homer, R. J., Ring, A., Wilen, C. B., & Iwasaki, A.
- Affiliations
- Yale University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Iwasaki, Akiko
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2020-08-04
- Volume
- 217
- Issue
- 12
- Pages
- 3628297-3628297
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC7401025
- OpenAlex
- W3046988613
- Cited by
- 415
- References
- 39
- Citations by year
- 2026: 14 · 2025: 22 · 2024: 38 · 2023: 66 · 2022: 88 · 2021: 129 · 2020: 58
- FWCI
- 11.17
- Type
- journal article
- Language
- en
- Update notices
- correction (2025-02-26)
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
- SSRN Electronic Journal (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- PubMed Central (submittedVersion)
- Funders
- National Institutes of Health (2T32AI007517-16, T32GM007205, F30CA239444, R37AI041699, AI054359, AI127429, T32AI007019, K08 AI128043)
- Women’s Health Research at Yale
- Mercatus Center
- G. Harold and Leila Y. Mathers Foundation
- Ludwig Family Foundation
- Howard Hughes Medical Institute
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Keywords
- SARS-CoV-2, COVID-19 pandemic, mouse model, adeno-associated virus, type I interferon signaling, viral replication, lung pathology, genetic background, animal model development
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