Identification of sialic acid-binding function for the Middle East respiratory syndrome coronavirus spike glycoprotein

Wentao Li, Ruben J.G. Hulswit, Ivy Widjaja, V.S. Raj, Ryan McBride, Wenjie Peng, W. Widagdo, M.A. Tortorici, Brenda van Dieren, Yifei Lang, Jan W.M. van Lent, James C. Paulson, Cornelis A.M. de Haan, Raoul J. de Groot, Frank J.M. Van Kuppeveld, Bart L. Haagmans*, Berend-Jan Bosch

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

135 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)E8508-E8517
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number40
DOIs
Publication statusPublished - 3 Oct 2017

Keywords

  • Attachment
  • MERS-CoV
  • Receptor
  • Sialic acid
  • Spike

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