Identification of sialic acid-binding function for the Middle East respiratory syndrome coronavirus spike glycoprotein
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.
|Keywords||Attachment, MERS-CoV, Receptor, Sialic acid, Spike|
|Persistent URL||dx.doi.org/10.1073/pnas.1712592114, hdl.handle.net/1765/108241|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
Li, W. (Wentao), Hulswit, R.J.G. (Ruben J. G.), Widjaja, I. (Ivy), Raj, V.S, McBride, R. (Ryan), Peng, W. (Wenjie), … 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. doi:10.1073/pnas.1712592114