Human Coronavirus HKU1 Spike Protein Uses O -Acetylated Sialic Acid as an Attachment Receptor Determinant and Employs Hemagglutinin-Esterase Protein as a Receptor-Destroying Enzyme

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Abstract
Human coronavirus (hCoV) HKU1 is one of six hCoVs identified to date and the only one with an unidentified cellular receptor. HCoV-HKU1 encodes a hemagglutinin-esterase (HE) protein that is unique to the betacoronaviruses group a (group 2a). The function of HKU1-HE remains largely undetermined. In this study, we examined binding of the S1 domain of hCoV-HKU1 spike to a panel of cells and found that the S1 could specifically bind on the cell surface of a human rhabdomyosarcoma cell line, RD. Pretreatment of RD cells with neuramidase (NA) and trypsin greatly reduced the binding, suggesting that the binding was mediated by sialic acids on glycoproteins. However, unlike other group 2a CoVs, e.g. hCoV-OC43 for which 9-O-acytylated sialic acid (9-O-Ac-Sia) servers as a receptor determinant, HKU1-S1 neither bound with 9-O-Ac-Sia containing glycoprotein(s), nor rat and mouse erythrocytes. Nonetheless, the HKU1-HE was similar to OC43-HE, also possessed sialate-O- acetylesterase activity and acted as a receptor-destroying enzyme (RDE) capable of eliminating the binding of HKU1-S1 to RD cells, whereas the O-acetylesterase inactive HKU1-HE mutant lost this capacity. Using primary human ciliated airway epithelial cell cultures (HAE), the only in vitro replication model for hCoV-HKU1 infection, we confirmed that pretreatment of HAE cells with HE but not the enzymatically inactive mutant blocked hCoV-HKU1 viral infection. These results demonstrate that hCoV-HKU1 exploits O-AC-Sia as a cellular attachment receptor determinant to initiate the infection of host cells, and its HE protein possesses the corresponding sialate-O-acetylesterase RDE activity.

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