Human coronavirus NL63 employs the severe acute respiratory syndrome coronavirus receptor for cellular entry
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Coronavirus (CoV) infection of humans is usually not associated with severe disease. However, discovery of the severe acute respiratory syndrome (SARS) CoV revealed that highly pathogenic human CoVs (HCoVs) can evolve. The identification and characterization of new HCoVs is, therefore, an important task. Recently, a HCoV termed NL63 was discovered in patients with respiratory tract illness. Here, cell tropism and receptor usage of HCoV-NL63 were analyzed. The NL63 spike (S) protein mediated infection of different target cells compared with the closely related 229E-S protein but facilitated entry into cells known to be permissive to SARS-CoV-S-driven infection. An analysis of receptor engagement revealed that NL63-S binds angiotensin-converting enzyme (ACE) 2, the receptor for SARS-CoV, and HCoV-NL63 uses ACE2 as a receptor for infection of target cells. Potent neutralizing activity directed against NL63- but not 229E-S protein was detected in virtually all sera from patients 8 years of age or older, suggesting that HCoV-NL63 infection of humans is common and usually acquired during childhood. Here, we show that SARS-CoV shares its receptor ACE2 with HCoV-NL63. Because the two viruses differ dramatically in their ability to induce disease, analysis of HCoV-NL63 might unravel pathogenicity factors in SARS-CoV. The frequent HCoV-NL63 infection of humans suggests that highly pathogenic variants have ample opportunity to evolve, underlining the need for vaccines against HCoVs.
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ACE2 also serves as the receptor for SARS-CoV and HCoV-NL63.
“Study of Zhou et al.4 indicated that the angiotensin-converting enzyme II (ACE2) is likely the cell receptor of 2019-nCoV, which were also the receptor for SARS-CoV and HCoV-NL637,8.”
From High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa (2020) · cites this paper as [8]
Cites
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
Characterization of a Novel Coronavirus Associated with Severe Acute Respiratory Syndrome
Rota, P. A., Oberste, M. S., Monroe, S. S., Nix, W. A., Campagnoli, R. P., Icenogle, J. P., Peñaranda, S., Bankamp, B., Maher, K., Chen, M., et al. (2003) · Science · doi:10.1126/science.1085952 · Cited by 2,477 · see citing works
The Genome Sequence of the SARS-Associated Coronavirus
Marra, M. A., Jones, S. J. M., Astell, C. R., Holt, R. A., Brooks-Wilson, A. R., Butterfield, Y. S. N., Khattra, J. S., Asano, J. K., Barber, S., Chan, S. Y., et al. (2003) · Science · doi:10.1126/science.1085953 · Cited by 2,017 · see citing works
Identification of a new human coronavirus
van der Hoek, L., Pyrć, K., Jebbink, M. F., Vermeulen-Oost, W., Berkhout, R. J. M., Wolthers, K. C., Dillen, P. M. E. W., Kaandorp, J. C., Spaargaren, J., & Berkhout, B. (2004) · Nature Medicine · doi:10.1038/nm1024 · Cited by 1,868 · see citing works
Self-citationAngiotensin-converting enzyme 2 is an essential regulator of heart function
Crackower, M. A., Sarao, R., Oudit, G. Y., Yagil, C., Kozieradzki, I., Scanga, S. E., Oliveira-dos-Santos, A. J., da Costa, J., Zhang, L., Pei, Y., et al. (2002) · Nature · doi:10.1038/nature00786 · Cited by 1,733 · see citing works
Bosch, B. J., van der Zee, R., de Haan, C. A. M., & Rottier, P. J. M. (2003) · Journal of Virology · doi:10.1128/jvi.77.16.8801-8811.2003 · Cited by 1,489 · see citing works
The Severe Acute Respiratory Syndrome
Peiris, J. S. M., Yuen, K., Osterhaus, A. D. M. E., & Stöhr, K. (2003) · New England Journal of Medicine · doi:10.1056/nejmra032498 · Cited by 1,377 · see citing works
Human aminopeptidase N is a receptor for human coronavirus 229E
Yeager, C. L., Ashmun, R. A., Williams, R. K., Cardellichio, C. B., Shapiro, L. H., Look, A. T., & Holmes, K. V. (1992) · Nature · doi:10.1038/357420a0 · Cited by 941 · see citing works
How Viruses Enter Animal Cells
Smith, A. E., & Helenius, A. (2004) · Science · doi:10.1126/science.1094823 · Cited by 735 · see citing works
Towler, P., Staker, B. L., Prasad, S. G., Menon, S., Tang, J., Parsons, T. F., Ryan, D., Fisher, M., Williams, D., Dales, N. A., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m311191200 · Cited by 699 · see citing works
Wong, S. K., Li, W., Moore, M. J., Choe, H., & Farzan, M. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.c300520200 · Cited by 690 · see citing works
Coronavirus Spike Proteins in Viral Entry and Pathogenesis
Gallagher, T. M., & Buchmeier, M. J. (2001) · Virology · doi:10.1006/viro.2000.0757 · Cited by 658 · see citing works
Aminopeptidase N is a major receptor for the enteropathogenic coronavirus TGEV
Delmas, B., Gelfi, J., L'Haridon, R., et al. (1992) · Nature · doi:10.1038/357417a0 · Cited by 634 · see citing works
Rice, G., Thomas, D. A., Grant, P. J., Turner, A. J., & Hooper, N. M. (2004) · Biochemical Journal · doi:10.1042/bj20040634 · Cited by 619 · see citing works
A previously undescribed coronavirus associated with respiratory disease in humans
Fouchier, R. A. M., Hartwig, N. G., Bestebroer, T. M., Niemeyer, B., de Jong, J. C., Simon, J. H., & Osterhaus, A. D. M. E. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0400762101 · Cited by 595 · see citing works
SARS — beginning to understand a new virus
Stadler, K., Masignani, V., Eickmann, M., Becker, S., Abrignani, S., Klenk, H., & Rappuoli, R. (2003) · Nature Reviews Microbiology · doi:10.1038/nrmicro775 · Cited by 558 · see citing works
Simmons, G., Reeves, J. D., Rennekamp, A. J., Amberg, S. M., Piefer, A. J., & Bates, P. F. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0306446101 · Cited by 543 · see citing works
Yang, Z., Huang, Y. M., Lakshmanan, G., Leung, K., Kong, W., Schwartz, O., Subbarao, K., & Nabel, G. J. (2004) · Journal of Virology · doi:10.1128/jvi.78.11.5642-5650.2004 · Cited by 488 · see citing works
Subbarao, K., McAuliffe, J. M., Vogel, L., Fahle, G. A., Fischer, S. H., Tatti, K. M., Packard, M. M., Shieh, W., Zaki, S. R., & Murphy, B. R. (2004) · Journal of Virology · doi:10.1128/jvi.78.7.3572-3577.2004 · Cited by 397 · see citing works
Association between a Novel Human Coronavirus and Kawasaki Disease
Esper, F. P., Shapiro, E. D., Weibel, C., Ferguson, D. J. P., Landry, M. L., & Kahn, J. S. (2005) · The Journal of Infectious Diseases · doi:10.1086/428291 · Cited by 394 · see citing works
Reverse genetics with a full-length infectious cDNA of severe acute respiratory syndrome coronavirus
Yount, B., Curtis, K. M., Fritz, E. A., Hensley, L. E., Jahrling, P., Prentice, E., Denison, M., Geisbert, T., & Baric, R. (2003) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1735582100 · Cited by 394 · see citing works
Kuo, L., Godeke, G.-J., Raamsman, M. J. B., Masters, P. S., & Rottier, P. J. M. (2000) · Journal of Virology · doi:10.1128/jvi.74.3.1393-1406.2000 · Cited by 366 · see citing works
Hofmann, H., Geier, M., Marzi, A., Krumbiegel, M., Peipp, M., Fey, G. H., Gramberg, T., & Pöhlmann, S. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.05.114 · Cited by 254 · see citing works
Self-citationCellular entry of the SARS coronavirus
Hofmann, H., & Pöhlmann, S. (2004) · Trends in Microbiology · doi:10.1016/j.tim.2004.08.008 · Cited by 238 · see citing works
Self-citationMoore, M. J., Dorfman, T., Li, W., Wong, S. K., Li, Y., Kuhn, J. H., Coderre, J. A., Vasilieva, N. Y., Han, Z., Greenough, T. C., et al. (2004) · Journal of Virology · doi:10.1128/jvi.78.19.10628-10635.2004 · Cited by 236 · see citing works
de Haan, C. A. M., Masters, P. S., Shen, X., Weiss, S. R., & Rottier, P. J. M. (2002) · Virology · doi:10.1006/viro.2002.1412 · Cited by 228 · see citing works
Esper, F. P., Weibel, C., Ferguson, D. J. P., Landry, M. L., & Kahn, J. S. (2005) · The Journal of Infectious Diseases · doi:10.1086/428138 · Cited by 218 · see citing works
Birkmann, A., Mahr, K., Ensser, A., Yağuboğlu, S., Titgemeyer, F., Fleckenstein, B., & Neipel, F. (2001) · Journal of Virology · doi:10.1128/jvi.75.23.11583-11593.2001 · Cited by 206 · see citing works
Arden, K. E., Nissen, M. D., Sloots, T. P., & Mackay, I. M. (2005) · Journal of Medical Virology · doi:10.1002/jmv.20288 · Cited by 203 · see citing works
Hofmann, H., Hattermann, K., Marzi, A., Gramberg, T., Geier, M., Krumbiegel, M., Kuate, S., Überla, K., Niedrig, M., & Pöhlmann, S. (2004) · Journal of Virology · doi:10.1128/jvi.78.12.6134-6142.2004 · Cited by 197 · see citing works
Self-citationMoës, E., Vijgen, L., Keyaerts, E., Zlateva, K. T., Li, S., Maes, P., Pyrć, K., Berkhout, B., van der Hoek, L., & Ranst, M. A. V. (2005) · BMC Infectious Diseases · doi:10.1186/1471-2334-5-6 · Cited by 176 · see citing works
Self-citationHuman Coronavirus NL63 Infection in Canada
Bastien, N., Anderson, K., Hart, L., Caeseele, P. G. V., Brandt, K., Milley, D., Hatchette, T. F., Weiss, E., & Li, Y. (2005) · The Journal of Infectious Diseases · doi:10.1086/426869 · Cited by 172 · see citing works
Li, W., Greenough, T. C., Moore, M. J., Vasilieva, N. Y., Somasundaran, M., Sullivan, J. L., Farzan, M., & Choe, H. (2004) · Journal of Virology · doi:10.1128/jvi.78.20.11429-11433.2004 · Cited by 167 · see citing works
Retroviral Vectors Pseudotyped with Severe Acute Respiratory Syndrome Coronavirus S Protein
Giroglou, T., Cinatl, J., Rabenau, H., Drosten, C., Schwalbe, H., Doerr, H., & von Laer, D. (2004) · Journal of Virology · doi:10.1128/jvi.78.17.9007-9015.2004 · Cited by 147 · see citing works
Expression cloning of functional receptor used by SARS coronavirus
Wang, P., Chen, J., Zheng, A., Nie, Y., Shi, X., Wang, W., Wang, G., Luo, M., Liu, H., Tan, L., et al. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.01.076 · Cited by 145 · see citing works
Detection of human coronavirus NL63 in young children with bronchiolitis
Ebihara, T., Endo, R., Ma, X., Ishiguro, N., & Kikuta, H. (2005) · Journal of Medical Virology · doi:10.1002/jmv.20289 · Cited by 115 · see citing works
Genome structure and transcriptional regulation of human coronavirus NL63
Pyrć, K., Jebbink, M. F., Berkhout, B., & van der Hoek, L. (2004) · Virology Journal · doi:10.1186/1743-422x-1-7 · Cited by 109 · see citing works
Self-citationNie, Y., Wang, P., Shi, X., Wang, G., Chen, J., Zheng, A., Wang, W., Wang, Z., Qu, X., Luo, M., et al. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.07.060 · Cited by 104 · see citing works
Danilczyk, U. G., Eriksson, U., Crackower, M. A., & Penninger, J. M. (2003) · Journal of Molecular Medicine · doi:10.1007/s00109-003-0419-x · Cited by 77 · see citing works
Human Coronavirus HCoV-229E Enters Susceptible Cells via the Endocytic Pathway
Blau, D. M., & Holmes, K. V. (2001) · Advances in experimental medicine and biology · doi:10.1007/978-1-4615-1325-4_31 · Cited by 74 · see citing works
Development of a safe neutralization assay for SARS-CoV and characterization of S-glycoprotein
Han, D. P., Kim, H. G., Kim, Y. B., et al. (2004) · Virology · doi:10.1016/j.virol.2004.05.017 · Cited by 66 · see citing works
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Self-citationStructural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2
Wang, Q., Zhang, Y., Wu, L., Niu, S., Song, C., Zhang, Z., Lu, G., Qiao, C., Hu, Y., Yuen, K.-Y., et al. (2020) · Cell · doi:10.1016/j.cell.2020.03.045 · Cited by 2,892 · see citing works
“Although they belong to different genera, SARS-CoV and hCoV-NL63 interact with human angiotensinconverting enzyme 2 (hACE2) for virus entry (Hofmann et al., 2005; Li et al., 2003; Wu et al., 2009).”
High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa
Xu, H., Zhong, L., Deng, J., Peng, J., Dan, H., Zeng, X., Li, T., & Chen, Q. (2020) · International Journal of Oral Science · doi:10.1038/s41368-020-0074-x · Cited by 2,838 · see citing works
Structure, Function, and Evolution of Coronavirus Spike Proteins
Li, F. (2016) · Annual Review of Virology · doi:10.1146/annurev-virology-110615-042301 · Cited by 2,740 · see citing works
Gheblawi, M., Wang, K., Viveiros, A., Nguyen, Q., Zhong, J.-C., Turner, A. J., Raizada, M. K., Grant, M. B., & Oudit, G. Y. (2020) · Circulation Research · doi:10.1161/circresaha.120.317015 · Cited by 1,882 · see citing works
Coronavirus Pathogenesis and the Emerging Pathogen Severe Acute Respiratory Syndrome Coronavirus
Weiss, S. R., & Navas-Martin, S. (2005) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.69.4.635-664.2005 · Cited by 1,256 · see citing works
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Ravindra, N. G., Alfajaro, M. M., Gasque, V., Huston, N. C., Wan, H., Szigeti-Buck, K., Yasumoto, Y., Greaney, A. M., Habet, V., Chow, R. D., et al. (2021) · PLOS Biology · doi:10.1371/journal.pbio.3001143 · Cited by 258 · see citing works
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Eguia, R., Crawford, K. H. D., Stevens-Ayers, T., Kelnhofer-Millevolte, L., Greninger, A. L., Englund, J. A., Boeckh, M. J., & Bloom, J. D. (2020) · doi:10.1101/2020.12.17.423313 · Cited by 258 · see citing works
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Beaudoin-Bussières, G., Laumaea, A., Anand, S. P., Prévost, J., Gasser, R., Goyette, G., Medjahed, H., Perreault, J., Tremblay, T., Lewin, A., et al. (2020) · mBio · doi:10.1128/mbio.02590-20 · Cited by 189 · see citing works
Zhou, W., Wang, W., Wang, H., Lu, R., & Tan, W. (2013) · BMC Infectious Diseases · doi:10.1186/1471-2334-13-433 · Cited by 124 · see citing works
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Devaux, C. A., & Camoin-Jau, L. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.1042200 · Cited by 20 · see citing works
- Authors
- Hofmann, H., Pyrc, K., van der Hoek, L., Geier, M., Berkhout, B., & Pöhlmann, S.
- Affiliations
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Institute for Clinical and Molecular Virology and Nikolaus Fiebiger Center, University Erlangen–Nürnberg, 91054 Erlangen, Germany; and Department of Human Retrovirology, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands
- Corresponding author
- Pöhlmann, Stefan
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-05-16
- Volume
- 102
- Issue
- 22
- Pages
- 7988-7993
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1142358
- OpenAlex
- W1965435260
- Cited by
- 824
- References
- 42
- Citations by year
- 2026: 19 · 2025: 45 · 2024: 55 · 2023: 59 · 2022: 81 · 2021: 149 · 2020: 200 · 2019: 4 · 2018: 8 · 2017: 7 · 2016: 20 · 2015: 11 · 2014: 29 · 2013: 18 · 2012: 9
- FWCI
- 15.03
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Health Sciences › Medicine › Epidemiology › Respiratory viral infections research
- Keywords
- HCoV-NL63, ACE2, spike protein, viral entry, receptor usage, cell tropism, HCoV-229E, neutralizing antibodies, pathogenicity, coronavirus evolution, coronavirus vaccines
- MeSH terms
- Angiotensin-Converting Enzyme 2, Carboxypeptidases, Cell Line, Flow Cytometry, Humans, Peptidyl-Dipeptidase A, Membrane Glycoproteins, Neutralization Tests, Plasmids, Receptors, Virus, Respiratory Tract Diseases, Species Specificity, Viral Envelope Proteins, Coronavirus Infections, Coronavirus 229E, Human, Severe acute respiratory syndrome-related coronavirus, Spike Glycoprotein, Coronavirus
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