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Journal of Virology, July 2006, p. 6305-6317, Vol. 80, No. 13
0022-538X/06/$08.00+0     doi:10.1128/JVI.02545-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The Signal Peptide of the Ebolavirus Glycoprotein Influences Interaction with the Cellular Lectins DC-SIGN and DC-SIGNR

Andrea Marzi,1,2 Armin Akhavan,3 Graham Simmons,4,5 Thomas Gramberg,1,2 Heike Hofmann,1,2,6 Paul Bates,4 Vishwanath R. Lingappa,3 and Stefan Pöhlmann1,2*

Institute for Clinical and Molecular Virology,1 Nikolaus-Fiebiger-Center, University Erlangen-Nürnberg, 91054 Erlangen, Germany,2 California Pacific Medical Center Research Institute, San Francisco, California,3 Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104,4 Blood Systems Research Institute, San Francisco, California 94118,5 Institute for Infection Medicine, University of Kiel, 24105 Kiel, Germany6

Received 5 December 2005/ Accepted 6 April 2006

The C-type lectins DC-SIGN and DC-SIGNR (collectively referred to as DC-SIGN/R) bind to the ebolavirus glycoprotein (EBOV-GP) and augment viral infectivity. DC-SIGN/R strongly enhance infection driven by the GP of EBOV subspecies. Zaire (ZEBOV) but have a much less pronounced effect on infection mediated by the GP of EBOV subspecies. Sudan (SEBOV). For this study, we analyzed the determinants of the differential DC-SIGN/R interactions with ZEBOV- and SEBOV-GP. The efficiency of DC-SIGN engagement by ZEBOV-GP was dependent on the rate of GP incorporation into lentiviral particles, while appreciable virion incorporation of SEBOV-GP did not allow robust DC-SIGN/R usage. Forced incorporation of high-mannose carbohydrates into SEBOV-GP augmented the engagement of DC-SIGN/R to the levels observed with ZEBOV-GP, indicating that appropriate glycosylation of SEBOV-GP is sufficient for efficient DC-SIGN/R usage. However, neither signals for N-linked glycosylation unique to SEBOV- or ZEBOV-GP nor the highly variable and heavily glycosylated mucin-like domain modulated the interaction with DC-SIGN/R. In contrast, analysis of chimeric GPs identified the signal peptide as a determinant of DC-SIGN/R engagement. Thus, ZEBOV- but not SEBOV-GP was shown to harbor high-mannose carbohydrates, and GP modification with these glycans was controlled by the signal peptide. These results suggest that the signal peptide governs EBOV-GP interactions with DC-SIGN/R by modulating the incorporation of high-mannose carbohydrates into EBOV-GP. In summary, we identified the level of GP incorporation into virions and signal peptide-controlled glycosylation of GP as determinants of attachment factor engagement.

* Corresponding author. Mailing address: Nikolaus-Fiebiger-Center, 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, July 2006, p. 6305-6317, Vol. 80, No. 13
0022-538X/06/$08.00+0     doi:10.1128/JVI.02545-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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