Does SARS‐Cov‐2 invade the brain? Translational lessons from animal models
Open accessAbstract
The current coronavirus disease (COVID‐19) outbreak, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has raised the possibility of potential neurotropic properties of this virus. Indeed, neurological sequelae of SARS‐CoV‐2 infection have already been reported and highlight the relevance of considering the neurological impact of coronavirus (CoV) from a translational perspective. Animal models of SARS and Middle East respiratory syndrome, caused by structurally similar CoVs during the 2002 and 2012 epidemics, have provided valuable data on nervous system involvement by CoVs and the potential for central nervous system spread of SARS‐CoV‐2. One key finding that may unify these pathogens is that all require angiotensin‐converting enzyme 2 as a cell entry receptor. The CoV spike glycoprotein, by which SARS‐CoV‐2 binds to cell membranes, binds angiotensin‐converting enzyme 2 with a higher affinity compared with SARS‐CoV. The expression of this receptor in neurons and endothelial cells hints that SARS‐CoV‐2 may have higher neuroinvasive potential compared with previous CoVs. However, it remains to be determined how such invasiveness might contribute to respiratory failure or cause direct neurological damage. Both direct and indirect mechanisms may be of relevance. Clinical heterogeneity potentially driven by differential host immune‐mediated responses will require extensive investigation. Development of disease models to anticipate emerging neurological complications and to explore mechanisms of direct or immune‐mediated pathogenicity in the short and medium term is therefore of great importance. In this brief review, we describe the current knowledge from models of previous CoV infections and discuss their potential relevance to COVID‐19.
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Evidence is accumulating suggesting that SARS-CoV-2 initially infects peripheral nerve terminals and, through a trans-synaptic mechanism, enters the CNS.
“In addition to the passage through the nasal neuro-epithelium route, independently from lower airway passage, evidence is accumulating suggesting that the virus initially infects peripheral nerve terminals and, through a trans-synaptic mechanism, enters the CNS [174].”
From Cognitive decline following acute viral infections: literature review and projections for post-COVID-19 (2022) · cites this paper as [174]
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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
Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation
Wrapp, D., Wang, N., Corbett, K. S., Goldsmith, J. A., Hsieh, C.-L., Abiona, O., Graham, B. S., & McLellan, J. S. (2020) · Science · doi:10.1126/science.abb2507 · Cited by 8,897 · see citing works
Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China
Mao, L., Jin, H., Wang, M., Hu, Y., Chen, S., He, Q., Chang, J., Hong, C., Zhou, Y., Wang, D., et al. (2020) · JAMA Neurology · doi:10.1001/jamaneurol.2020.1127 · Cited by 7,166 · see citing works
Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus
Li, W., Moore, M. J., Vasilieva, N., Sui, J., Wong, S. K., Berne, M. A., Somasundaran, M., Sullivan, J. L., Luzuriaga, K., Greenough, T. C., et al. (2003) · Nature · doi:10.1038/nature02145 · Cited by 5,923 · see citing works
Hamming, I., Timens, W., Bulthuis, M., Lely, A., Navis, G., & van Goor, H. (2004) · The Journal of Pathology · doi:10.1002/path.1570 · Cited by 5,676 · see citing works
A Novel Coronavirus Associated with Severe Acute Respiratory Syndrome
Tg, K., Erdman, D. D., Cs, G., Zaki, Peret, T. C. T., Emery, S. L., Tong, S., Urbani, C., Comer, J. A., Lim, W., et al. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa030781 · Cited by 4,345 · see citing works
Li, Y., Bai, W., & Hashikawa, T. (2020) · Journal of Medical Virology · doi:10.1002/jmv.25728 · Cited by 2,266 · see citing works
Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC
Raj, V. S., Mou, H., Smits, S. L., Dekkers, D. H. W., Müller, M. A., Dijkman, R., Muth, D., Demmers, J. A. A., Zaki, A., Fouchier, R. A. M., et al. (2013) · Nature · doi:10.1038/nature12005 · Cited by 2,061 · see citing works
COVID-19–associated Acute Hemorrhagic Necrotizing Encephalopathy: Imaging Features
Poyiadji, N., Shahin, G., Noujaim, D., Stone, M., Patel, S., & Griffith, B. (2020) · Radiology · doi:10.1148/radiol.2020201187 · Cited by 1,505 · see citing works
Multiple organ infection and the pathogenesis of SARS
Gu, J., Gong, E., Zhang, B., Zheng, J., Gao, Z., Zhong, Y., Zou, W., Zhan, J., Wang, S., Xie, Z., et al. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20050828 · Cited by 1,379 · see citing works
Netland, J., Meyerholz, D. K., Moore, S., Cassell, M., & Perlman, S. (2008) · Journal of Virology · doi:10.1128/jvi.00737-08 · Cited by 1,293 · see citing works
Tian, X., Li, C., Huang, A., Xia, S., Lu, S., Shi, Z., Lu, L., Jiang, S., Yang, Z., Wu, Y., et al. (2020) · Emerging Microbes & Infections · doi:10.1080/22221751.2020.1729069 · Cited by 1,239 · see citing works
Brann, D. H., Tsukahara, T., Weinreb, C., Lipovsek, M., Van den Berge, K., Gong, B., Chance, R., Macaulay, I. C., Chou, H.-J., Fletcher, R. B., et al. (2020) · Science Advances · doi:10.1126/sciadv.abc5801 · Cited by 1,198 · 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
Glowacka, I., Bertram, S., Müller, M. A., Allen, P. W., Soilleux, E. J., Pfefferle, S., Steffen, I., Tsegaye, T. S., He, Y., Gnirß, K., et al. (2011) · Journal of Virology · doi:10.1128/jvi.02232-10 · Cited by 1,109 · see citing works
Ding, Y., He, L., Zhang, Q., Huang, Z., Che, X., Hou, J., Wang, H., Shen, H., Qiu, L., Li, Z., et al. (2004) · The Journal of Pathology · doi:10.1002/path.1560 · Cited by 1,068 · see citing works
McCray, P. B., Pewe, L., Wohlford-Lenane, C., Hickey, M., Manzel, L., Shi, L., Netland, J., Jia, H. P., Halabi, C., Sigmund, C. D., et al. (2007) · Journal of Virology · doi:10.1128/jvi.02012-06 · Cited by 1,010 · see citing works
Guillain-Barré syndrome associated with SARS-CoV-2 infection: causality or coincidence?
Zhao, H., Shen, D., Zhou, H., Liu, J., & Chen, S. (2020) · The Lancet Neurology · doi:10.1016/s1474-4422(20)30109-5 · Cited by 987 · see citing works
de Wit, E., Feldmann, F., Cronin, J., Jordan, R., Okumura, A., Thomas, T., Scott, D. P., Cihlář, T., & Feldmann, H. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1922083117 · Cited by 888 · see citing works
Quantitative mRNA expression profiling of ACE 2, a novel homologue of angiotensin converting enzyme
Harmer, D., Gilbert, M., Borman, R., & Clark, K. L. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)03640-2 · Cited by 852 · see citing works
Structure of MERS-CoV spike receptor-binding domain complexed with human receptor DPP4
Wang, N., Shi, X., Jiang, L., Zhang, S., Wang, D., Tong, P., Guo, D., Fu, L., Cui, Y., Liu, X., et al. (2013) · Cell Research · doi:10.1038/cr.2013.92 · Cited by 719 · see citing works
Neurologic alterations due to respiratory virus infections
Bohmwald, K., Gálvez, N. M. S., Ríos, M., & Kalergis, A. M. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00386 · Cited by 636 · see citing works
Neuroinvasion by Human Respiratory Coronaviruses
Arbour, N., Day, R. W., Newcombe, J., & Talbot, P. J. (2000) · Journal of Virology · doi:10.1128/jvi.74.19.8913-8921.2000 · Cited by 518 · see citing works
Immunopathogenesis of coronavirus infections: implications for SARS
Dandekar, A. A., & Perlman, S. M. (2005) · Nature reviews. Immunology · doi:10.1038/nri1732 · Cited by 499 · see citing works
Neurological complications during treatment of middle east respiratory syndrome
Kim, J.-E., Heo, J.-H., Kim, H.-O., Song, S.-H., Park, S.-S., Park, T.-H., Ahn, J.-Y., Kim, M.-K., & Choi, J.-P. (2017) · Journal of Clinical Neurology · doi:10.3988/jcn.2017.13.3.227 · Cited by 497 · see citing works
Zhou, J., Chu, H., Li, C., Wong, B. H., Cheng, Z., Poon, V. K., Sun, T., Lau, C. C.-Y., Wong, K. K. Y., Chan, J. Y. W., et al. (2013) · The Journal of Infectious Diseases · doi:10.1093/infdis/jit504 · Cited by 425 · see citing works
Doobay, M. F., Talman, L. S., Obr, T. D., Tian, X., Davisson, R. L., & Lazartigues, E. D. (2006) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00292.2006 · Cited by 407 · see citing works
Coronavirus infection of the central nervous system: host–virus stand-off
Bergmann, C. C., Lane, T. E., & Stohlman, S. A. (2006) · Nature Reviews Microbiology · doi:10.1038/nrmicro1343 · Cited by 398 · see citing works
Possible Central Nervous System Infection by SARS Coronavirus
Lau, K., Yu, W.-C., Chu, C., Lau, S.-T., Sheng, B., & Yuen, K. (2004) · Emerging infectious diseases · doi:10.3201/eid1002.030638 · Cited by 395 · see citing works
Severe neurologic syndrome associated with Middle East respiratory syndrome corona virus (MERS-CoV)
Arabi, Y. M., Alharthi, A. F., Hussein, J., Bouchama, A., Johani, S. A., Hajeer, A. H., Saeed, B. T., Wahbi, A. M. A., Saedy, A., Aldabbagh, T., et al. (2015) · Infection · doi:10.1007/s15010-015-0720-y · Cited by 389 · see citing works
Glass, W. G., Subbarao, K., Murphy, B. R., & Murphy, P. M. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.6.4030 · Cited by 337 · see citing works
Yeh, E. A., Collins, A. R., Cohen, M. E., Duffner, P. K., & Faden, H. S. (2004) · PEDIATRICS · doi:10.1542/peds.113.1.e73 · Cited by 329 · see citing works
de Wit, E., Rasmussen, A. L., Falzarano, D., Bushmaker, T., Feldmann, F., Brining, D. L., Fischer, E. R., Martellaro, C., Okumura, A., Chang, J., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1310744110 · Cited by 312 · see citing works
Brann, D. H., Tsukahara, T., Weinreb, C., Lipovsek, M., den Berge, K. V., Gong, B., Chance, R., Macaulay, I. C., Chou, H.-J., Fletcher, R., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.03.25.009084 · Cited by 294 · see citing works
Human coronaviruses: Viral and cellular factors involved in neuroinvasiveness and neuropathogenesis
Desforges, M., Coupanec, A. L., Stodola, J. K., Meessen-Pinard, M., & Talbot, P. J. (2014) · Virus Research · doi:10.1016/j.virusres.2014.09.011 · Cited by 274 · see citing works
What’s new in the renin-angiotensin system?
Kuhn, J. H., Li, W., Choe, H., & Farzan, M. (2004) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-004-4242-5 · Cited by 250 · see citing works
Hung, E. C. W., Chim, S. S. C., Chan, P. K. S., Tong, Y. K., Ng, E. K. O., Chiu, R. W. K., Leung, C., Sung, J. J. �., Tam, J. S., & Lo, Y. M. D. (2003) · Clinical Chemistry · doi:10.1373/clinchem.2003.025437 · Cited by 247 · see citing works
Infection with novel coronavirus (SARS-CoV-2) causes pneumonia in Rhesus macaques
Shan, C., Yao, Y., Yang, X., Zhou, Y., Gao, G., Peng, Y., Yang, L., Hu, X., Xiong, J., Jiang, R.-D., et al. (2020) · Cell Research · doi:10.1038/s41422-020-0364-z · Cited by 241 · see citing works
Chan, J. F., Chan, K., Choi, G. K.-Y., To, K. K., Tse, H., Cai, J., Yeung, M. L., Cheng, V. C., Chen, H., Che, X.-Y., et al. (2013) · The Journal of Infectious Diseases · doi:10.1093/infdis/jit123 · Cited by 219 · see citing works
Agrawal, A. S., Garron, T. M., Tao, X., Peng, B., Wakamiya, M., Chan, T., Couch, R. B., & Tseng, C.-T. K. (2015) · Journal of Virology · doi:10.1128/jvi.03427-14 · Cited by 208 · see citing works
Animal models for SARS and MERS coronaviruses
Gretebeck, L., & Subbarao, K. (2015) · Current Opinion in Virology · doi:10.1016/j.coviro.2015.06.009 · Cited by 181 · see citing works
Chan, R. W. Y., Chan, M. C. W., Agnihothram, S., et al. (2013) · Journal of Virology · doi:10.1128/jvi.00009-13 · Cited by 169 · see citing works
Li, Y., Fu, L., Gonzales, D. M., & Lavi, E. (2004) · Journal of Virology · doi:10.1128/jvi.78.7.3398-3406.2004 · Cited by 158 · see citing works
Hogan, R. J., Gao, G., Rowe, T., Bell, P. L., Flieder, D. B., Paragas, J., Kobinger, G., Wivel, N. A., Crystal, R. G., Boyer, J. L., et al. (2004) · Journal of Virology · doi:10.1128/jvi.78.20.11416-11421.2004 · Cited by 132 · see citing works
Interaction of severe acute respiratory syndrome-associated coronavirus with dendritic cells
Spiegel, M., Schneider, K., Weber, F., Weidmann, M., & Hufert, F. T. (2006) · Journal of General Virology · doi:10.1099/vir.0.81624-0 · Cited by 130 · see citing works
Wagner, L., Klemann, C., Stephan, M., et al. (2015) · Clinical & Experimental Immunology · doi:10.1111/cei.12757 · Cited by 114 · see citing works
Livestock Susceptibility to Infection with Middle East Respiratory Syndrome Coronavirus
Vergara‐Alert, J., van den Brand, J. M. A., Widagdo, W., et al. (2016) · Emerging infectious diseases · doi:10.3201/eid2302.161239 · Cited by 110 · see citing works
Is there an ideal animal model for SARS?
Subbarao, K., & Roberts, A. (2006) · Trends in Microbiology · doi:10.1016/j.tim.2006.05.007 · Cited by 104 · see citing works
The Pathogenicity of SARS-CoV-2 in hACE2 Transgenic MicePreprint
Bao, L., Deng, W., Huang, B., Gao, H., Liu, J., Ren, L., Wei, Q., Yu, P., Xu, Y., Qi, F., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.02.07.939389 · Cited by 79 · see citing works
The battle against SARS and MERS coronaviruses: Reservoirs and Animal Models
Gong, S., & Bao, L. (2018) · Animal Models and Experimental Medicine · doi:10.1002/ame2.12017 · Cited by 64 · see citing works
Pathogenicity and Viral Shedding of MERS-CoV in Immunocompromised Rhesus Macaques
Prescott, J. B., Falzarano, D., de Wit, E., Hardcastle, K., Feldmann, F., Haddock, E., Scott, D. P., Feldmann, H., & Munster, V. J. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00205 · Cited by 50 · see citing works
Susceptibility of human and rat neural cell lines to infection by SARS-coronavirus
Yamashita, M., Yamate, M., Li, G., & Ikuta, K. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.06.061 · Cited by 48 · see citing works
Labs rush to study coronavirus in transgenic animals — some are in short supply
Callaway, E. (2020) · Nature · doi:10.1038/d41586-020-00698-x · Cited by 45 · see citing works
Tackling dipeptidyl peptidase IV in neurological disorders
Castorina, A., Al‐Badri, G., Leggio, G. M., Musumeci, G., Marzagalli, R., & Drago, F. (2018) · Neural Regeneration Research · doi:10.4103/1673-5374.224365 · Cited by 34 · see citing works
A Comparative Review of Animal Models of Middle East Respiratory Syndrome Coronavirus Infection
Baseler, L. J., de Wit, E., & Feldmann, H. (2016) · Veterinary Pathology · doi:10.1177/0300985815620845 · Cited by 28 · see citing works
Hao, X., Lv, Q., Li, F., Xu, Y., & Gao, H. (2019) · Animal Models and Experimental Medicine · doi:10.1002/ame2.12088 · Cited by 21 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- Li W, Moore MJ, Vasilieva N, et al. Angiotensin-con- verting enzyme 2: a functional receptor for SARS coron- avirus. Nature 2003; 426: 450-454.
- Kim JE, Heo JH, Kim HO, et al. Neurological compli- cations during treatment of middle east respiratory syn- drome. J Clin Neurol 2017; 13: 227-233.
Cited by
Sorted by citations
Miskowiak, K., Johnsen, S., Sattler, S., Nielsen, S., Kunalan, K., Rungby, J., Lapperre, T., & Porsberg, C. (2021) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2021.03.019 · Cited by 365 · see citing works
Residual clinical damage after COVID-19: a retrospective and prospective observational cohort study
De Lorenzo, R., Conte, C., Lanzani, C., Benedetti, F., Roveri, L., Mazza, M. G., Brioni, E., Giacalone, G., Canti, V., Sofia, V., et al. (2020) · PLoS ONE · doi:10.1371/journal.pone.0239570 · Cited by 179 · see citing works
Negrini, F., Ferrario, I., Mazziotti, D., Berchicci, M., Bonazzi, M., de Sire, A., Negrini, S., & Zapparoli, L. (2021) · Archives of Physical Medicine and Rehabilitation · doi:10.1016/j.apmr.2020.09.376 · Cited by 121 · see citing works
Damiano, R. F., Guedes, B. F., de Rocca, C. C., de Pádua Serafim, A., Castro, L. H. M., Munhoz, C. D., Nitrini, R., Filho, G. B., Miguel, E. C., Lucchetti, G., et al. (2022) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-021-01286-4 · Cited by 98 · see citing works
Rabinovitz, B., Jaywant, A., & Fridman, C. B. (2020) · The Clinical Neuropsychologist · doi:10.1080/13854046.2020.1803408 · Cited by 46 · see citing works
- Authors
- Natoli, S., Oliveira, V., Calabresi, P., Maia, L. F., & Pisani, A.
- Affiliations
- University of Rome Tor Vergata (IT)
- Centro Hospitalar do Porto (PT)
- Agostino Gemelli University Polyclinic (IT)
- Department of Neurology Centro Hospitalar Universitário do Porto Porto Portugal
- Corresponding author
- Pisani, A.
- Venue
- European Journal of Neurology
- Publisher
- Wiley
- Published
- 2020-05-22
- Volume
- 27
- Issue
- 9
- Pages
- 1764-1773
- ISSN
- 1351-5101 (ISSN-L)
- 1468-1331
- PMC
- PMC7267377
- OpenAlex
- W3020676731
- Cited by
- 260
- References
- 56
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 11 · 2023: 21 · 2022: 49 · 2021: 79 · 2020: 87
- FWCI
- 6.63
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Neurology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion, other-oa)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Neurology › Long-Term Effects of COVID-19
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Health Sciences › Medicine › Infectious Diseases › Infectious Encephalopathies and Encephalitis
- Keywords
- SARS-CoV-2, COVID-19 pandemic, neurotropism, central nervous system infiltration, angiotensin-converting enzyme 2, spike protein, SARS-CoV, MERS-CoV, animal models, neurological complications, respiratory failure, host immune response
- MeSH terms
- COVID-19, SARS-CoV-2, Animals, Brain, Humans, Models, Animal, Endothelial Cells, Translational Research, Biomedical
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