Recent H3N2 Viruses Have Evolved Specificity for Extended, Branched Human-type Receptors, Conferring Potential for Increased Avidity

• Published in: Cell host & microbe Vol. 21; no. 1; pp. 23 - 34
• Main Authors: Peng, Wenjie, de Vries, Robert P., Grant, Oliver C., Thompson, Andrew J., McBride, Ryan, Tsogtbaatar, Buyankhishig, Lee, Peter S., Razi, Nahid, Wilson, Ian A., Woods, Robert J., Paulson, James C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.01.2017
• Subjects: airway; Animals; bidentate binding; Cell Line; chemo-enzymatic synthesis; Dogs; extended branched glycans; Galactans - metabolism; H3N2; HEK293 Cells; hemagglutinin; Hemagglutinin Glycoproteins, Influenza Virus - metabolism; Humans; Influenza A Virus, H1N1 Subtype - genetics; Influenza A Virus, H1N1 Subtype - metabolism; Influenza A Virus, H3N2 Subtype - genetics; Influenza A Virus, H3N2 Subtype - metabolism; Influenza A Virus, H3N8 Subtype - metabolism; Influenza A Virus, H5N1 Subtype - metabolism; influenza virus; Madin Darby Canine Kidney Cells; Molecular Dynamics Simulation; N-Acetylneuraminic Acid - metabolism; poly-N-acetyl-lactosamine; Polysaccharides - metabolism; receptor specificity; Receptors, Virus - metabolism; sialoside microarray; Species Specificity; Virus Attachment; sialoside microarray; chemo-enzymatic synthesis; poly-N-acetyl-lactosamine; bidentate binding; hemagglutinin; airway; influenza virus; receptor specificity; extended branched glycans; H3N2
• DOI: 10.1016/j.chom.2016.11.004
• ISSN: 1931-3128; 1934-6069

Human and avian influenza viruses recognize different sialic acid-containing receptors, referred to as human-type (NeuAcα2-6Gal) and avian-type (NeuAcα2-3Gal), respectively. This presents a species barrier for aerosol droplet transmission of avian viruses in humans and ferrets. Recent reports have suggested that current human H3N2 viruses no longer have strict specificity toward human-type receptors. Using an influenza receptor glycan microarray with extended airway glycans, we find that H3N2 viruses have in fact maintained human-type specificity, but they have evolved preference for a subset of receptors comprising branched glycans with extended poly-N-acetyl-lactosamine (poly-LacNAc) chains, a specificity shared with the 2009 pandemic H1N1 (Cal/04) hemagglutinin. Lipid-linked versions of extended sialoside receptors can restore susceptibility of sialidase-treated MDCK cells to infection by both recent (A/Victoria/361/11) and historical (A/Hong Kong/8/1968) H3N2 viruses. Remarkably, these human-type receptors with elongated branches have the potential to increase avidity by simultaneously binding to two subunits of a single hemagglutinin trimer. [Display omitted] •All H3N2 influenza viruses recognize human-type receptors with extended glycan chains•Recent H3 and pandemic H1 hemagglutinins prefer extended, branched N-glycan receptors•Lipid-linked glycan receptors restore infectivity to receptor-deficient MDCK cells•Molecular dynamics simulation shows bidentate binding of N-glycans to one HA trimer To clarify H3N2 human influenza virus receptor specificity, Peng et al. developed a glycan array that included extended glycans. Recent H3N2 and 2009 pandemic H1N1 viruses share specificity for human-type receptors with extended glycan chains, conferring potential for increased avidity by simultaneously binding two subunits of a single hemagglutinin trimer.