title: Quantitative biochemical rationale for differences in transmissibility of 1918 pandemic influenza A viruses.
abstract: The human adaptation of influenza A viruses is critically governed by the binding specificity of the viral surface hemagglutinin (HA) to long (chain length) alpha2-6 sialylated glycan (alpha2-6) receptors on the human upper respiratory tissues. A recent study demonstrated that whereas the 1918 H1N1 pandemic virus, A/South Carolina/1/1918 (SC18), with alpha2-6 binding preference transmitted efficiently, a single amino acid mutation on HA resulted in a mixed alpha2-3 sialylated glycan (alpha2-3)/alpha2-6 binding virus (NY18) that transmitted inefficiently. To define the biochemical basis for the observed differences in virus transmission, in this study, we have developed an approach to quantify the multivalent HA-glycan interactions. Analysis of the molecular HA-glycan contacts showed subtle changes resulting from the single amino acid variations between SC18 and NY18. The effect of these changes on glycan binding is amplified by multivalency, resulting in quantitative differences in their long alpha2-6 glycan binding affinities. Furthermore, these differences are also reflected in the markedly distinct binding pattern of SC18 and NY18 HA to the physiological glycans present in human upper respiratory tissues. Thus, the dramatic lower binding affinity of NY18 to long alpha2-6 glycans, as against a mixed alpha2-3/6 binding, correlates with its inefficient transmission. In summary, this study establishes a quantitative biochemical correlate for influenza A virus transmission.
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Aravind
authors.initials: A
authors.lastname: Srinivasan
authors.forename: Karthik
authors.initials: K
authors.lastname: Viswanathan
authors.forename: Rahul
authors.initials: R
authors.lastname: Raman
authors.forename: Aarthi
authors.initials: A
authors.lastname: Chandrasekaran
authors.forename: S
authors.initials: S
authors.lastname: Raguram
authors.forename: Terrence M
authors.initials: TM
authors.lastname: Tumpey
authors.forename: V
authors.initials: V
authors.lastname: Sasisekharan
authors.forename: Ram
authors.initials: R
authors.lastname: Sasisekharan
mesh_terms: D016367:Baculoviridae; D004196:Disease Outbreaks; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000378:metabolism*; D049673:History, 20th Century; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000378:metabolism*; D007251:Influenza, Human / Q000453:epidemiology* / Q000266:history* / Q000635:transmission*; D008958:Models, Molecular; D016296:Mutagenesis; D011134:Polysaccharides / Q000378:metabolism; D011485:Protein Binding; D014132:Trachea / Q000166:cytology / Q000378:metabolism
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011134:Polysaccharides; C483468:hemagglutinin, human influenza A virus