title: The GD1a glycan is a cellular receptor for adenoviruses causing epidemic keratoconjunctivitis.
abstract: Adenovirus type 37 (Ad37) is a leading cause of epidemic keratoconjunctivitis (EKC), a severe and highly contagious ocular disease. Whereas most other adenoviruses infect cells by engaging CD46 or the coxsackie and adenovirus receptor (CAR), Ad37 binds previously unknown sialic acid-containing cell surface molecules. By glycan array screening, we show here that the receptor-recognizing knob domain of the Ad37 fiber protein specifically binds a branched hexasaccharide that is present in the GD1a ganglioside and that features two terminal sialic acids. Soluble GD1a glycan and GD1a-binding antibodies efficiently prevented Ad37 virions from binding and infecting corneal cells. Unexpectedly, the receptor is constituted by one or more glycoproteins containing the GD1a glycan motif rather than the ganglioside itself, as shown by binding, infection and flow cytometry experiments. Molecular modeling, nuclear magnetic resonance and X-ray crystallography reveal that the two terminal sialic acids dock into two of three previously established sialic acid-binding sites in the trimeric Ad37 knob. Surface plasmon resonance analysis shows that the knob-GD1a glycan interaction has high affinity. Our findings therefore form a basis for the design and development of sialic acid-containing antiviral drugs for topical treatment of EKC.
authors.affiliation: Department of Clinical Microbiology, Division of Virology, Umeå University, Umeå, Sweden.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Nilsson
authors.forename: Rickard J
authors.initials: RJ
authors.lastname: Storm
authors.forename: Johannes
authors.initials: J
authors.lastname: Bauer
authors.forename: Susanne M C
authors.initials: SM
authors.lastname: Johansson
authors.forename: Aivar
authors.initials: A
authors.lastname: Lookene
authors.forename: Jonas
authors.initials: J
authors.lastname: Ångström
authors.forename: Mattias
authors.initials: M
authors.lastname: Hedenström
authors.forename: Therese L
authors.initials: TL
authors.lastname: Eriksson
authors.forename: Lars
authors.initials: L
authors.lastname: Frängsmyr
authors.forename: Simon
authors.initials: S
authors.lastname: Rinaldi
authors.forename: Hugh J
authors.initials: HJ
authors.lastname: Willison
authors.forename: Fatima
authors.initials: F
authors.lastname: Pedrosa Domellöf
authors.forename: Thilo
authors.initials: T
authors.lastname: Stehle
authors.forename: Niklas
authors.initials: N
authors.lastname: Arnberg
mesh_terms: D000257:Adenoviridae Infections / Q000453:epidemiology*; D000998:Antiviral Agents / Q000627:therapeutic use; D001665:Binding Sites; D002462:Cell Membrane / Q000821:virology; D018360:Crystallography, X-Ray; D019573:Epithelium, Corneal / Q000821:virology; D005677:G(M1) Ganglioside / Q000031:analogs & derivatives* / Q000737:chemistry / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007637:Keratoconjunctivitis / Q000188:drug therapy / Q000453:epidemiology / Q000276:immunology / Q000821:virology*; D008958:Models, Molecular; D011485:Protein Binding; D011991:Receptors, Virus / Q000502:physiology*; D012794:Sialic Acids / Q000378:metabolism / Q000627:therapeutic use; D020349:Surface Plasmon Resonance
chemical_list: D000998:Antiviral Agents; D011991:Receptors, Virus; D012794:Sialic Acids; C085301:adenovirus receptor; C064020:ganglioside GD1alpha; D005677:G(M1) Ganglioside