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Identification of sialic acid-binding function for the Middle East respiratory syndrome coronavirus spike glycoprotein.
Proc Natl Acad Sci U S A. 2017 10 03; 114(40):E8508-E8517.PN

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) targets the epithelial cells of the respiratory tract both in humans and in its natural host, the dromedary camel. Virion attachment to host cells is mediated by 20-nm-long homotrimers of spike envelope protein S. The N-terminal subunit of each S protomer, called S1, folds into four distinct domains designated S1A through S1D Binding of MERS-CoV to the cell surface entry receptor dipeptidyl peptidase 4 (DPP4) occurs via S1B We now demonstrate that in addition to DPP4, MERS-CoV binds to sialic acid (Sia). Initially demonstrated by hemagglutination assay with human erythrocytes and intact virus, MERS-CoV Sia-binding activity was assigned to S subdomain S1A When multivalently displayed on nanoparticles, S1 or S1A bound to human erythrocytes and to human mucin in a strictly Sia-dependent fashion. Glycan array analysis revealed a preference for α2,3-linked Sias over α2,6-linked Sias, which correlates with the differential distribution of α2,3-linked Sias and the predominant sites of MERS-CoV replication in the upper and lower respiratory tracts of camels and humans, respectively. Binding is hampered by Sia modifications such as 5-N-glycolylation and (7,)9-O-acetylation. Depletion of cell surface Sia by neuraminidase treatment inhibited MERS-CoV entry of Calu-3 human airway cells, thus providing direct evidence that virus-Sia interactions may aid in virion attachment. The combined observations lead us to propose that high-specificity, low-affinity attachment of MERS-CoV to sialoglycans during the preattachment or early attachment phase may form another determinant governing the host range and tissue tropism of this zoonotic pathogen.

Authors+Show Affiliations

Virology Division, Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands.Virology Division, Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands.Virology Division, Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands.Department of Viroscience, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands.Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037. Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037. Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037. Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037. Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037.Department of Viroscience, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands.Institut Pasteur, Unité de Virologie Structurale, 75015 Paris, France. CNRS UMR 3569 Virologie, 75015 Paris, France.Virology Division, Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands.Virology Division, Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands.Laboratory of Virology, Department of Plant Sciences, Wageningen University, 6708 PB Wageningen, The Netherlands.Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037.Virology Division, Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands.Virology Division, Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands.Virology Division, Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands.Department of Viroscience, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands; b.haagmans@erasmusmc.nl b.j.bosch@uu.nl.Virology Division, Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands; b.haagmans@erasmusmc.nl b.j.bosch@uu.nl.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28923942

Citation

Li, Wentao, et al. "Identification of Sialic Acid-binding Function for the Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein." Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 40, 2017, pp. E8508-E8517.
Li W, Hulswit RJG, Widjaja I, et al. Identification of sialic acid-binding function for the Middle East respiratory syndrome coronavirus spike glycoprotein. Proc Natl Acad Sci U S A. 2017;114(40):E8508-E8517.
Li, W., Hulswit, R. J. G., Widjaja, I., Raj, V. S., McBride, R., Peng, W., Widagdo, W., Tortorici, M. A., van Dieren, B., Lang, Y., van Lent, J. W. M., Paulson, J. C., de Haan, C. A. M., de Groot, R. J., van Kuppeveld, F. J. M., Haagmans, B. L., & Bosch, B. J. (2017). Identification of sialic acid-binding function for the Middle East respiratory syndrome coronavirus spike glycoprotein. Proceedings of the National Academy of Sciences of the United States of America, 114(40), E8508-E8517. https://doi.org/10.1073/pnas.1712592114
Li W, et al. Identification of Sialic Acid-binding Function for the Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein. Proc Natl Acad Sci U S A. 2017 10 3;114(40):E8508-E8517. PubMed PMID: 28923942.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of sialic acid-binding function for the Middle East respiratory syndrome coronavirus spike glycoprotein. AU - Li,Wentao, AU - Hulswit,Ruben J G, AU - Widjaja,Ivy, AU - Raj,V Stalin, AU - McBride,Ryan, AU - Peng,Wenjie, AU - Widagdo,W, AU - Tortorici,M Alejandra, AU - van Dieren,Brenda, AU - Lang,Yifei, AU - van Lent,Jan W M, AU - Paulson,James C, AU - de Haan,Cornelis A M, AU - de Groot,Raoul J, AU - van Kuppeveld,Frank J M, AU - Haagmans,Bart L, AU - Bosch,Berend-Jan, Y1 - 2017/09/18/ PY - 2017/9/20/pubmed PY - 2018/6/27/medline PY - 2017/9/20/entrez KW - MERS-CoV KW - attachment KW - receptor KW - sialic acid KW - spike SP - E8508 EP - E8517 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 114 IS - 40 N2 - Middle East respiratory syndrome coronavirus (MERS-CoV) targets the epithelial cells of the respiratory tract both in humans and in its natural host, the dromedary camel. Virion attachment to host cells is mediated by 20-nm-long homotrimers of spike envelope protein S. The N-terminal subunit of each S protomer, called S1, folds into four distinct domains designated S1A through S1D Binding of MERS-CoV to the cell surface entry receptor dipeptidyl peptidase 4 (DPP4) occurs via S1B We now demonstrate that in addition to DPP4, MERS-CoV binds to sialic acid (Sia). Initially demonstrated by hemagglutination assay with human erythrocytes and intact virus, MERS-CoV Sia-binding activity was assigned to S subdomain S1A When multivalently displayed on nanoparticles, S1 or S1A bound to human erythrocytes and to human mucin in a strictly Sia-dependent fashion. Glycan array analysis revealed a preference for α2,3-linked Sias over α2,6-linked Sias, which correlates with the differential distribution of α2,3-linked Sias and the predominant sites of MERS-CoV replication in the upper and lower respiratory tracts of camels and humans, respectively. Binding is hampered by Sia modifications such as 5-N-glycolylation and (7,)9-O-acetylation. Depletion of cell surface Sia by neuraminidase treatment inhibited MERS-CoV entry of Calu-3 human airway cells, thus providing direct evidence that virus-Sia interactions may aid in virion attachment. The combined observations lead us to propose that high-specificity, low-affinity attachment of MERS-CoV to sialoglycans during the preattachment or early attachment phase may form another determinant governing the host range and tissue tropism of this zoonotic pathogen. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/28923942/Identification_of_sialic_acid_binding_function_for_the_Middle_East_respiratory_syndrome_coronavirus_spike_glycoprotein_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=28923942 DB - PRIME DP - Unbound Medicine ER -