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Journal of Virology, September 2006, p. 8639-8652, Vol. 80, No. 17
0022-538X/06/$08.00+0     doi:10.1128/JVI.00560-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Highly Conserved Regions within the Spike Proteins of Human Coronaviruses 229E and NL63 Determine Recognition of Their Respective Cellular Receptors

Heike Hofmann,1,2,3 Graham Simmons,4,5 Andrew J. Rennekamp,4 Chawaree Chaipan,1,2 Thomas Gramberg,1,2 Elke Heck,1,2 Martina Geier,1,2 Anja Wegele,1,2 Andrea Marzi,1,2 Paul Bates,4 and Stefan Pöhlmann1,2*

Institute for Clinical and Molecular Virology,1 Nikolaus-Fiebiger-Center, University Erlangen-Nürnberg, 91054 Erlangen, Germany,2 Institute for Infection Medicine, University of Kiel, 24105 Kiel, Germany,3 Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania,4 Blood Systems Research Institute, San Francisco, California 941185

Received 17 March 2006/ Accepted 12 June 2006

We have recently demonstrated that the severe acute respiratory syndrome coronavirus (SARS-CoV) receptor angiotensin converting enzyme 2 (ACE2) also mediates cellular entry of the newly discovered human coronavirus (hCoV) NL63. Here, we show that expression of DC-SIGN augments NL63 spike (S)-protein-driven infection of susceptible cells, while only expression of ACE2 but not DC-SIGN is sufficient for entry into nonpermissive cells, indicating that ACE2 fulfills the criteria of a bona fide hCoV-NL63 receptor. As for SARS-CoV, murine ACE2 is used less efficiently by NL63-S for entry than human ACE2. In contrast, several amino acid exchanges in human ACE2 which diminish SARS-S-driven entry do not interfere with NL63-S-mediated infection, suggesting that SARS-S and NL63-S might engage human ACE2 differentially. Moreover, we observed that NL63-S-driven entry was less dependent on a low-pH environment and activity of endosomal proteases compared to infection mediated by SARS-S, further suggesting differences in hCoV-NL63 and SARS-CoV cellular entry. NL63-S does not exhibit significant homology to SARS-S but is highly related to the S-protein of hCoV-229E, which enters target cells by engaging CD13. Employing mutagenic analyses, we found that the N-terminal unique domain in NL63-S, which is absent in 229E-S, does not confer binding to ACE2. In contrast, the highly homologous C-terminal parts of the NL63-S1 and 229E-S1 subunits in conjunction with distinct amino acids in the central regions of these proteins confer recognition of ACE2 and CD13, respectively. Therefore, despite the high homology of these sequences, they likely form sufficiently distinct surfaces, thus determining receptor specificity.

* Corresponding author. Mailing address: University Erlangen-Nürnberg, Nikolaus-Fiebiger-Center for Molecular Medicine, Glückstraße 6, 91054 Erlangen, Germany. Phone: 49 9131 8529142. Fax: 49 9131 8529111. E-mail: snpoehlm{at}viro.med.uni-erlangen.de.

Journal of Virology, September 2006, p. 8639-8652, Vol. 80, No. 17
0022-538X/06/$08.00+0     doi:10.1128/JVI.00560-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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