SARS-CoV-2 infection of human ACE2-transgenic mice causes severe lung inflammation and impaired function
Open accessAbstract
Although animal models have been evaluated for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, none have fully recapitulated the lung disease phenotypes seen in humans who have been hospitalized. Here, we evaluate transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lungs, with spread to other organs. A decline in pulmonary function occurs 4 days after peak viral titer and correlates with infiltration of monocytes, neutrophils and activated T cells. SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with signatures of nuclear factor-κB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection shares many features of severe COVID-19 infection and can be used to define the basis of lung disease and test immune and antiviral-based countermeasures.
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In a humanized transgenic mouse model, ACE2 was expressed in the heart and virus replication detected, but they did not observe cardiac inflammation.
“In a humanized transgenic mouse model, ACE2 was expressed in the heart and virus replication detected, but they did not observe cardiac inflammation. 181”
From COVID-19, Myocarditis and Pericarditis (2023) · cites this paper as [181]
Extended Data Fig. 1 reports hACE2 expression measurements in the heart, and the Discussion reports moderate levels of viral RNA there. The Results section on extra-pulmonary histopathology describes abnormalities in 2 of 9 hearts but does not report cardiac inflammatory infiltrates. The claim overstates the viral finding as detected replication: the cited passages establish viral RNA in the heart, not productive replication there. (LLM, conf=0.84)
Experimental — accuracy not yet measuredK18-hACE2 transgenic mice have a human ACE2 receptor which is the major cell entry receptor for SARS-CoV-2.
“These transgenic mice have a human ACE2 receptor which is the major cell entry receptor for SARS-CoV-216,17.”
From Efficacy of an unmodified bivalent mRNA vaccine against SARS-CoV-2 variants in female small animal models (2023) · cites this paper as [17]
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Self-citationUnderstanding COVID-19-associated coagulopathy
Conway, E. M., Mackman, N., Warren, R. Q., Wolberg, A. S., Mosnier, L. O., Campbell, R. A., Gralinski, L. E., Rondina, M. T., van de Veerdonk, F. L., Hoffmeister, K. M., et al. (2022) · Nature reviews. Immunology · doi:10.1038/s41577-022-00762-9 · Cited by 362 · see citing works
Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A
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Lessons learned 1 year after SARS-CoV-2 emergence leading to COVID-19 pandemic
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Macrophage phenotypes and functions: resolving inflammation and restoring homeostasis
Rodríguez-Morales, P., & Franklin, R. A. (2023) · Trends in Immunology · doi:10.1016/j.it.2023.10.004 · Cited by 327 · see citing works
Patients with COVID-19: in the dark-NETs of neutrophils
Ackermann, M., Anders, H., Bilyy, R. O., Bowlin, G. L., Daniel, C., LORENZO, R. D., Egeblad, M., Henneck, T., Hidalgo, A., Hoffmann, M. H., et al. (2021) · Cell Death and Differentiation · doi:10.1038/s41418-021-00805-z · Cited by 307 · see citing works
“Neutrophils also infiltrate alveolar and interstitial areas of K18-hACE2 transgenic mice infected with SARS-CoV-2 leading to a comparable pulmonary pathology [32, 99].”
BackgroundCoinfection with influenza A virus enhances SARS-CoV-2 infectivity
Bai, L., Zhao, Y., Dong, J., Liang, S., Guo, M. S., Liu, X., Wang, X., Huang, Z., Sun, X., Zhang, Z., et al. (2021) · Cell Research · doi:10.1038/s41422-021-00473-1 · Cited by 298 · see citing works
Neuroinvasion and Encephalitis Following Intranasal Inoculation of SARS-CoV-2 in K18-hACE2 Mice
Kumari, P., Rothan, H. A., Natekar, J. P., Stone, S., Pathak, H., Strate, P. G., Arora, K., Brinton, M. A., & Kumar, M. (2021) · Viruses · doi:10.3390/v13010132 · Cited by 296 · see citing works
“These studies were focused on describing the acute lung injury in SARS-CoV-2 infected K18-hACE2 mice that was associated with high levels of inflammatory cytokines and accumulation of immune cells in the lungs [22-25].”
BackgroundResultInfluentialCharacterization and antiviral susceptibility of SARS-CoV-2 Omicron BA.2
Uraki, R., Kiso, M., Iida, S., Imai, M., Takashita, E., Kuroda, M., Halfmann, P., Loeber, S. J., Maemura, T., Yamayoshi, S., et al. (2022) · Nature · doi:10.1038/s41586-022-04856-1 · Cited by 277 · see citing works
Self-citationThe interferon landscape along the respiratory tract impacts the severity of COVID-19
Sposito, B., Broggi, A., Pandolfi, L., Crotta, S., Clementi, N., Ferrarese, R., Sisti, S., Criscuolo, E., Spreafico, R., Long, J. M., et al. (2021) · Cell · doi:10.1016/j.cell.2021.08.016 · Cited by 264 · see citing works
Mosaic RBD nanoparticles protect against challenge by diverse sarbecoviruses in animal models
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“Target list [bead region] were as follows: T helper: GM-CSF [44], IFN gamma [43], IL-1 beta [18], IL-2 [19], IL-4 [20], IL-5 [21], IL-6 [25], IL-8 (CXCL8) [27], IL-10 [28], IL12p70 [34], IL-13 [35], IL-17A (CTLA-8) [36], IL-18 [66], IL-23 [63], TNF alpha [45] Cytokines: CD40L [74], G-CSF (CSF-3) [42], IFN alpha [48],…”
Brain motor and fear circuits regulate leukocytes during acute stress
Poller, W. C., Downey, J., Mooslechner, A. A., Khan, N., Li, L., Chan, C. T., McAlpine, C. S., Xu, C., Kahles, F., He, S., et al. (2022) · Nature · doi:10.1038/s41586-022-04890-z · Cited by 234 · see citing works
A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic
Shapira, T., Monreal, I. A., Dion, S. P., Buchholz, D. W., Imbiakha, B., Olmstead, A. D., Jager, M. C., Désilets, A., Gao, G., Martins, M., et al. (2022) · Nature · doi:10.1038/s41586-022-04661-w · Cited by 239 · see citing works
In vivo monoclonal antibody efficacy against SARS-CoV-2 variant strains
Chen, R. E., Winkler, E. S., Case, J. B., Aziati, I. D., Bricker, T. L., Joshi, A., Darling, T. L., Ying, B., Errico, J. M., Shrihari, S., et al. (2021) · Nature · doi:10.1038/s41586-021-03720-y · Cited by 209 · see citing works
Self-citationLimited cross-variant immunity from SARS-CoV-2 Omicron without vaccination
Suryawanshi, R. K., Chen, I. P., Ma, T., Syed, A. M., Brazer, N., Saldhi, P., Simoneau, C. R., Ciling, A., Khalid, M. M., Sreekumar, B. K. N., et al. (2022) · Nature · doi:10.1038/s41586-022-04865-0 · Cited by 208 · see citing works
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“K18-hACE2 mice also display lung inflammation, cytokine storm, and impaired respiratory function (Winkler et al., 2020).”
SARS-CoV-2 replication in airway epithelia requires motile cilia and microvillar reprogramming
Wu, C.-T., Lidsky, P. V., Xiao, Y., Cheng, R., Lee, I. T., Nakayama, T., Jiang, S., He, W., Demeter, J., Garcia-Knight, M., et al. (2022) · Cell · doi:10.1016/j.cell.2022.11.030 · Cited by 208 · see citing works
Comparison of transgenic and adenovirus hACE2 mouse models for SARS-CoV-2 infection
Rathnasinghe, R., Strohmeier, S., Amanat, F., Gillespie, V., Krammer, F., García‐Sastre, A., Coughlan, L., Schotsaert, M., & Uccellini, M. B. (2020) · Emerging Microbes & Infections · doi:10.1080/22221751.2020.1838955 · Cited by 197 · see citing works
“In addition, the K18-hACE2 model resulted in more severe disease [58], manifesting in weight loss, and replication in multiple organs –”
Adaptive immune determinants of viral clearance and protection in mouse models of SARS-CoV-2
Israelow, B., Mao, T., Klein, J., Song, E., Menasche, B., Omer, S. B., & Iwasaki, A. (2021) · Science Immunology · doi:10.1126/sciimmunol.abl4509 · Cited by 189 · see citing works
“For these experiments, we utilized the K18 hACE2 mice (transgenic mice that express human ACE2) model, as they represent a lethal disease model of SARS-CoV-2 (24, 25).”
Pharmacological activation of STING blocks SARS-CoV-2 infection
Li, M., Ferretti, M., Ying, B., Descamps, H. C., Lee, E. M., Dittmar, M., Lee, J. S., Whig, K., Kamalia, B., Dohnalová, L., et al. (2021) · Science Immunology · doi:10.1126/sciimmunol.abi9007 · Cited by 186 · see citing works
Self-citationAdaptive immune determinants of viral clearance and protection in mouse models of SARS-CoV-2
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Drug combination therapy for emerging viral diseases
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Self-citationType-I-interferon-responsive microglia shape cortical development and behavior
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COVID-19, Myocarditis and Pericarditis
Fairweather, D., Beetler, D. J., Di Florio, D. N., Musigk, N., Heidecker, B., & Cooper, L. T. (2023) · Circulation Research · doi:10.1161/circresaha.123.321878 · Cited by 181 · see citing works
SARS-CoV-2 ferritin nanoparticle vaccines elicit broad SARS coronavirus immunogenicity
Joyce, M. G., Chen, W., Sankhala, R. S., Hajduczki, A., Thomas, P. V., Choe, M., Martinez, E. J., Chang, W. C., Peterson, C. E., Morrison, E. B., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.110143 · Cited by 179 · see citing works
Self-citationEicosanoid signalling blockade protects middle-aged mice from severe COVID-19
Wong, L.-Y. R., Zheng, J., Wilhelmsen, K., Li, K., Ortiz, M. E., Schnicker, N. J., Thurman, A., Pezzulo, A. A., Szachowicz, P. J., Li, P., et al. (2022) · Nature · doi:10.1038/s41586-022-04630-3 · Cited by 178 · see citing works
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“Other studies have identified a similar transcriptional response in human ACE2 (hACE2)-transgenic mice and in mice transduced with hACE2-encoding adenovirus-based vectors or by using a mouse-adapted strain of SARS-CoV-2 (Dinnon et al., 2020; Israelow et al., 2020; Sun et al., 2020; Winkler et al., 2020).”
Polymer nanoparticles deliver mRNA to the lung for mucosal vaccination
Suberi, A., Grun, M. K., Mao, T., Israelow, B., Reschke, M., Grundler, J., Akhtar, L., Lee, T., Shin, K., Piotrowski-Daspit, A. S., et al. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.abq0603 · Cited by 184 · see citing works
JAK-STAT Pathway Inhibition and their Implications in COVID-19 Therapy
Satarker, S., Tom, A. A., Shaji, R. A., Alosious, A., Luvis, M., & Nampoothiri, M. (2020) · Postgraduate Medicine · doi:10.1080/00325481.2020.1855921 · Cited by 170 · see citing works
“Interestingly, reports have demonstrated the significant pathogenic potential of SARS-CoV-2 when evaluated in hACE2 transgenic mice [38,39] Upon SARS-CoV-2 infection in K18 type of hACE2 (K18-hACE2)-transgenic mice, high amounts of viral RNA was detected in the lungs accompanied by increased levels of pro-inflammatory…”
BackgroundDefining the risk of SARS-CoV-2 variants on immune protection
DeGrace, M. M., Ghedin, E., Frieman, M. B., Krammer, F., Grifoni, A., Alisoltani, A., Alter, G., Amara, R. R., Baric, R. S., Barouch, D. H., et al. (2022) · Nature · doi:10.1038/s41586-022-04690-5 · Cited by 167 · see citing works
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Self-citationNeutrophils in respiratory viral infections
Johansson, C., & Kirsebom, F. C. M. (2021) · Mucosal Immunology · doi:10.1038/s41385-021-00397-4 · Cited by 163 · see citing works
A diamidobenzimidazole STING agonist protects against SARS-CoV-2 infection
Humphries, F., Shmuel-Galia, L., Jiang, Z., Wilson, R., Landis, P., Ng, S., Parsi, K. M., Maehr, R., Cruz, J., Morales-Ramos, Á. I., et al. (2021) · Science Immunology · doi:10.1126/sciimmunol.abi9002 · Cited by 159 · see citing works
Targeting stem-loop 1 of the SARS-CoV-2 5′ UTR to suppress viral translation and Nsp1 evasion
Vora, S. M., Fontana, P., Mao, T., Leger, V., Zhang, Y., Fu, T., Lieberman, J., Gehrke, L., Shi, M., Wang, L., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2117198119 · Cited by 159 · see citing works
“This finding is consistent with our analysis on the Nsp1 NT-CT linker deletion mutant as well as with other naturally isolated SARS-CoV-2 NT deletion mutants which were associated with lower viral titres and less severe COVID-19 disease (Lin et al., 2021).”
MethodCutting Edge: Nucleocapsid Vaccine Elicits Spike-Independent SARS-CoV-2 Protective Immunity
Matchett, W. E., Joag, V., Stolley, J. M., Shepherd, F. K., Quarnstrom, C. F., Mickelson, C. K., Wijeyesinghe, S., Soerens, A. G., Becker, S., Thiede, J. M., et al. (2021) · The Journal of Immunology · doi:10.4049/jimmunol.2100421 · Cited by 148 · see citing works
COVID-19 and cellular senescence
Schmitt, C. A., Tchkonia, T., Niedernhofer, L. J., Robbins, P. D., Kirkland, J. L., & Lee, S. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-022-00785-2 · Cited by 153 · see citing works
Impaired ketogenesis ties metabolism to T cell dysfunction in COVID-19
Karagiannis, F., Peukert, K., Surace, L., Michla, M., Nikolka, F., Fox, M., Weiss, P., Feuerborn, C., Maier, P., Schulz, S., et al. (2022) · Nature · doi:10.1038/s41586-022-05128-8 · Cited by 146 · see citing works
Interactions of SARS-CoV-2 with the Blood–Brain Barrier
Erickson, M. A., Rhea, E. M., Knopp, R. C., & Banks, W. A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052681 · Cited by 150 · see citing works
Combining spike- and nucleocapsid-based vaccines improves distal control of SARS-CoV-2
Dangi, T., Class, J., Palacio, N. M., Richner, J. M., & Penaloza‐MacMaster, P. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109664 · Cited by 145 · see citing works
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“5f) 4,43,62–64 .”
Pharmacological inhibition of fatty acid synthesis blocks SARS-CoV-2 replication
Chu, J., Xing, C., Du, Y., Duan, T., Liu, S., Zhang, P., Cheng, C., Henley, J. E., Liu, X., Chen, Q., et al. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00479-4 · Cited by 138 · see citing works
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Neurological complications and infection mechanism of SARS-CoV-2
Wan, D., Du, T., Hong, W., Chen, L., Que, H., Lu, S., & Peng, X. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00818-7 · Cited by 132 · see citing works
“The studies in mice models using human ACE2 expression that monitored the arrival time of virus in different brain structures revealed that SARS-CoV-2 infection in olfactory bulbs was not more than other brain structures, such as the brainstem, hypothalamus, and thalamic nuclei.(249,253,254) The limitation of engineer…”
BackgroundMeasuring immunity to SARS-CoV-2 infection: comparing assays and animal models
Khoury, D. S., Wheatley, A. K., Ramuta, M. D., Reynaldi, A., Cromer, D., Subbarao, K., O’Connor, D. H., Kent, S. J., & Davenport, M. P. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-020-00471-1 · Cited by 115 · see citing works
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Intravenous administration of BCG protects mice against lethal SARS-CoV-2 challenge
Hilligan, K. L., Namasivayam, S., Clancy, C. S., O’Mard, D., Oland, S. D., Robertson, S. J., Baker, P. J., Castro, E., Garza, N. L., Lafont, B. A. P., et al. (2021) · The Journal of Experimental Medicine · doi:10.1084/jem.20211862 · Cited by 123 · see citing works
“In keeping with published datasets, SCV2 infection drove a marked induction of proinflammatory cytokines, including IL-6, GMCSF, IL-12p70, and TNF-α, in transgenic mice (Winkler et al., 2020), while BCG i.”
An intranasal vaccine durably protects against SARS-CoV-2 variants in mice
Hassan, A. O., Shrihari, S., Gorman, M. J., Ying, B., Yuan, D., Raju, S., Chen, R. E., Dmitriev, I. P., Kashentseva, E. A., Adams, L. J., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109452 · Cited by 129 · see citing works
Self-citationSARS-CoV-2 Infection of Microglia Elicits Proinflammatory Activation and Apoptotic Cell Death
Jeong, G. U., Lyu, J., Kim, K., Chung, Y. C., Yoon, G. Y., Lee, S., Hwang, I., Shin, W.-H., Ko, J., Lee, J., et al. (2022) · Microbiology Spectrum · doi:10.1128/spectrum.01091-22 · Cited by 125 · see citing works
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“In some of the mouse models expressing human ACE2, the timing of arrival of the virus in various brain structures was monitored, and it was described that olfactory bulbs were infected not more than other parts of the brain, especially the hypothalamus and other thalamic nuclei, and the brainstem [21, 101, 104]—simila…”
BackgroundResultHuang, H.-Y., Liao, H.-Y., Chen, X., Wang, S.-W., Cheng, C.-W., Shahed-Al-Mahmud, M., Liu, Y.-M., Mohapatra, A., Chen, T.-H., Lo, J. M., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abm0899 · Cited by 118 · see citing works
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Development of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 3CLpro
Hou, N., Shuai, L., Zhang, L., Xie, X., Tang, K., Zhu, Y., Yin, Y., Zhang, W., Tan, Q., Zhong, G., et al. (2023) · ACS Central Science · doi:10.1021/acscentsci.2c01359 · Cited by 122 · see citing works
TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation
Ho, J., Mok, B. W.-Y., Campisi, L., Jordan, T. X., Yildiz, S., Parameswaran, S., Wayman, J. A., Gaudreault, N. N., Meekins, D. A., Indran, S. V., et al. (2021) · Cell · doi:10.1016/j.cell.2021.03.051 · Cited by 121 · see citing works
“As such, K18-hACE2 has been suggested as a model to define the basis of SARS-CoV-2-induced lung disease and test immune and antiviral countermeasures (Bao et al., 2020; Winkler et al., 2020).”
Animal Models for COVID-19: Hamsters, Mouse, Ferret, Mink, Tree Shrew, and Non-human Primates
Shou, S., Liu, M., Yang, Y., Kang, N., Song, Y., Tan, D., Liu, N.-N., Wang, F., Liu, J., & Xie, Y.-H. (2021) · Frontiers in Microbiology · doi:10.3389/fmicb.2021.626553 · Cited by 112 · see citing works
Differential roles of interferons in innate responses to mucosal viral infections
Walker, F. C., Sridhar, P., & Baldridge, M. T. (2021) · Trends in Immunology · doi:10.1016/j.it.2021.09.003 · Cited by 127 · see citing works
“Further, type III IFNs have been implicated as a potential part of the ‘cytokine storm’ associated with SARS-CoV-2-induced morbidity and mortality in human ACE2 transgenic mice [87,117,118].”
BackgroundGuimond, S. E., Mycroft‐West, C. J., Gandhi, N. S., Tree, J. A., Le, T. T., Spalluto, C. M., Humbert, M. V., Buttigieg, K. R., Coombes, N. S., Elmore, M. J., et al. (2022) · ACS Central Science · doi:10.1021/acscentsci.1c01293 · Cited by 120 · see citing works
Sensing of cytoplasmic chromatin by cGAS activates innate immune response in SARS-CoV-2 infection
Zhou, Z. L., Zhang, X., Lei, X., Xiao, X., Jiao, T., Ma, R., Dong, X., Jiang, Q., Wang, W., Shi, Y., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00800-3 · Cited by 118 · see citing works
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Endothelial cell infection and dysfunction, immune activation in severe COVID-19
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Neuroinvasion and Neurotropism by SARS-CoV-2 Variants in the K18-hACE2 Mouse
Seehusen, F., Clark, J. J., Sharma, P., Bentley, E. G., Kirby, A., Subramaniam, K. S., Wunderlin-Giuliani, S., Hughes, G. L., Patterson, E. I., Michael, B. D., et al. (2022) · Viruses · doi:10.3390/v14051020 · Cited by 112 · see citing works
“This might also explain the activation/hypertrophy of astrocytes in areas with perivascular infiltrates and the diffuse microglial activation and multifocal microgliosis that we and others observed [42,55,63].”
BackgroundIsolation and characterization of cross-neutralizing coronavirus antibodies from COVID-19+ subjects
Jennewein, M. F., MacCamy, A. J., Akins, N. R., Feng, J., Homad, L. J., Hurlburt, N. K., Seydoux, E., Wan, Y.-H., Stuart, A. B., Edara, V. V., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109353 · Cited by 105 · see citing works
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“mice, which develop severe lung infection and disease after intranasal inoculation (Golden et al., 2020; Winkler et al., 2020; Zheng et al., 2021).”
Self-citationCharacterization of SARS-CoV-2 Omicron BA.4 and BA.5 isolates in rodents
Uraki, R., Halfmann, P., Iida, S., Yamayoshi, S., Furusawa, Y., Kiso, M., Ito, M., Iwatsuki‐Horimoto, K., Mine, S., Kuroda, M., et al. (2022) · Nature · doi:10.1038/s41586-022-05482-7 · Cited by 106 · see citing works
Animal models for COVID-19: advances, gaps and perspectives
Fan, C., Wu, Y., Xiong, R., Yang, Y., Ling, C., Liu, S., Liu, S., & Wang, Y. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01087-8 · Cited by 104 · see citing works
“In particular, several chemokines (CCL2, CCL3, CCL4, CXCL1, and CXCL10) and inflammatory cytokines (TNFα, IL-6, and G-CSF) associated with the severity of COVID-19 disease in humans are highly expressed in these models.(221,236,242,243) In aged mice, the interferon and adaptive antibody responses to the SARS-CoV-2 cha…”
BackgroundNatural and Experimental SARS-CoV-2 Infection in Domestic and Wild Animals
Meekins, D., Gaudreault, N., & Richt, J. (2021) · Viruses · doi:10.3390/v13101993 · Cited by 87 · see citing works
“Severe lung pathology is characteristic for the SARS-CoV-2 infected K18-hACE2 mice [143,145–147,149,216], along with virus detected in upper and lower respiratory tract samples [143,146,147,149,216].”
BackgroundAnimal models in SARS-CoV-2 research
Chu, H., Chan, J. F.-W., & Yuen, K.-Y. (2022) · Nature Methods · doi:10.1038/s41592-022-01447-w · Cited by 103 · see citing works
García‐Arriaza, J., Garaigorta, U., Pérez, P., Lázaro-Frías, A., Zamora, C., Gastaminza, P., del Fresno, C., Casasnovas, J. M., Sorzano, C. Ó. S., Sancho, D., et al. (2021) · Journal of Virology · doi:10.1128/jvi.02260-20 · Cited by 100 · see citing works
“Next, we analyzed the efficacy of the MVA-S vaccine candidate in K18-hACE2 mice, a mouse model for SARS-CoV-2 infection and lethality (44, 45).”
MethodRadvák, P., Kwon, H., Košíková, M., Ortega‐Rodriguez, U., Xiang, R., Phue, J., Shen, R., Rozzelle, J., Kapoor, N., Rabara, T. R., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26803-w · Cited by 93 · see citing works
Wang, S., Li, W., Wang, Z., Yang, W., Li, E., Xia, X., Yan, F., & Chiu, S. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01917-x · Cited by 117 · see citing works
Chan, C. E. Z., Seah, S. G. K., Chye, D. H., Massey, S., Torres, M., Lim, A. P. C., Wong, S. K. K., Neo, J. J. Y., Wong, P. S., Lim, J. H., et al. (2021) · PLoS ONE · doi:10.1371/journal.pone.0253487 · Cited by 89 · see citing works
Temporal omics analysis in Syrian hamsters unravel cellular effector responses to moderate COVID-19
Nouailles, G., Wyler, E., Pennitz, P., Postmus, D., Vladimirova, D., Kazmierski, J., Pott, F., Dietert, K., Mülleder, M., Farztdinov, V. M., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-25030-7 · Cited by 98 · see citing works
Carossino, M., Kenney, D., O’Connell, A. K., Montanaro, P., Tseng, A. E., Gertje, H. P., Grosz, K. A., Ericsson, M., Huber, B. R., Kurnick, S. A., et al. (2022) · Viruses · doi:10.3390/v14030535 · Cited by 94 · see citing works
“respiratory disease observed in severe cases of COVID-19 diagnosed with ARDS [28,36].”
BackgroundResultInfluentialFumagalli, V., Ravà, M., Marotta, D., Lucia, P. D., Laura, C., Sala, E., Grillo, M., Bono, E. B., Giustini, L., Perucchini, C., et al. (2022) · Science Immunology · doi:10.1126/sciimmunol.abl9929 · Cited by 91 · see citing works
“Indeed, and in line with previous studies ( 18 – 20 ), viral RNA and viral antigens were detected in the olfactory bulb of IN-infected, but not AR-infected, mice ( Fig.”
Wysocki, J. A., Ye, M., Hassler, L., Gupta, A., Wang, Y., Nicoleascu, V., Randall, G. C., Wertheim, J. A., & BATLLE, D. C. (2021) · Journal of the American Society of Nephrology · doi:10.1681/asn.2020101537 · Cited by 96 · see citing works
Dampalla, C. S., Zheng, J. H., Perera, K. D., Wong, L.-Y. R., Meyerholz, D. K., Nguyen, H. N., Kashipathy, M. M., Battaile, K. P., Lovell, S., Kim, Y., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2101555118 · Cited by 96 · see citing works
An aberrant immune–epithelial progenitor niche drives viral lung sequelae
Narasimhan, H., Cheon, I. S., Qian, W., Hu, S. S., Parimon, T., Li, C., Goplen, N. P., Wu, Y., Wei, X., Son, Y. M., et al. (2024) · Nature · doi:10.1038/s41586-024-07926-8 · Cited by 104 · see citing works
“Finally, we infected transgenic mice expressing the human ACE2 receptor under the cytokeratin 18 promoter (K18-hACE2) with the wild-type SARS-CoV-2 virus (USA-WA1/2020), which is known to result in perivascular and alveolar inflammation 34 (Extended Data Fig.”
VanBlargan, L. A., Adams, L., Liu, Z.-M., Chen, R. E., Gilchuk, P., Raju, S., Smith, B. K., Zhao, H.-Y., Case, J., Winkler, E. S., et al. (2021) · Immunity · doi:10.1016/j.immuni.2021.08.016 · Cited by 95 · see citing works
“To further evaluate the level of protection conferred by a subset of mAbs in our panel, we measured levels of cytokines and chemokines in lung tissues at 7 dpi, which are markers of the inflammatory and pathological outcomes in this mouse model (Golden et al., 2020; Oladunni et al., 2020; Winkler et al., 2020; Yinda e…”
Self-citationAn intranasal ASO therapeutic targeting SARS-CoV-2
Zhu, C., Lee, J. Y., Woo, J. Z., Xu, L., Wrynla, X. H., Yamashiro, L. H., Ji, F., Biering, S. B., Dis, E. S. V., Gonzãlez, F., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-32216-0 · Cited by 97 · see citing works
Bentley, E. G., Kirby, A., Sharma, P., Kipar, A., Mega, D. F., Bramwell, C., Penrice-Randal, R., Prince, T., Brown, J. C., Zhou, J., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.12.26.474085 · Cited by 94 · see citing works
- Authors
- Winkler, 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., Ritter, J. H., Kang, L.-I., Dort, S., Robichaud, A., Head, R., Holtzman, M. J., & Diamond, M. S.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Diamond, Michael S.
- ORCID
- Venue
- Nature Immunology
- Published
- 2020-08-24
- Volume
- 21
- Issue
- 11
- Pages
- 1327-1335
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC7578095
- OpenAlex
- W3080378920
- Cited by
- 901
- References
- 56
- Citations by year
- 2026: 55 · 2025: 72 · 2024: 124 · 2023: 131 · 2022: 234 · 2021: 252 · 2020: 32
- FWCI
- 21.20
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-09-02)
- Open access
- bronze
- doi.org
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (75N93019C00062, R01 AI127828, R01 AI130591, R35 HL145242, F32 AI138392)
- United States Department of Defense | Defense Advanced Research Projects Agency (HR001117S0019)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- SARS-CoV-2, COVID-19 pandemic, K18-hACE2 mice, animal model of COVID-19, lung inflammation, lung function decline, monocytes, neutrophils, T cell activation, innate immune response, interferon signaling, NF-κB signaling
- MeSH terms
- Betacoronavirus, Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, Animals, Chlorocebus aethiops, Disease Models, Animal, Female, Humans, Immunity, Innate, Interferon Type I, Interferon-gamma, Peptidyl-Dipeptidase A, Leukocytes, Lymphocyte Activation, Male, Mice, Transgenic, Monocytes, Neutrophils, Pneumonia, Pneumonia, Viral, Promoter Regions, Genetic, T-Lymphocytes, Vero Cells, Virus Replication, NF-kappa B, Coronavirus Infections, Neutrophil Infiltration, Mice, Keratin-18, Pandemics
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