title: Networks link antigenic and receptor-binding sites of influenza hemagglutinin: mechanistic insight into fitter strain propagation.
abstract: Influenza viral passaging through pre-vaccinated mice shows that emergent antigenic site mutations on the viral hemagglutinin (HA) impact host receptor-binding affinity and, therefore, the evolution of fitter influenza strains. To understand this phenomenon, we computed the Significant Interactions Network (SIN) for each residue and mapped the networks of antigenic site residues on a representative H1N1 HA. Specific antigenic site residues are 'linked' to receptor-binding site (RBS) residues via their SIN and mutations within "RBS-linked" antigenic residues can significantly influence receptor-binding affinity by impacting the SIN of key RBS residues. In contrast, other antigenic site residues do not have such "RBS-links" and do not impact receptor-binding affinity upon mutation. Thus, a potential mechanism emerges for how immunologic pressure on RBS-linked antigenic residues can contribute to evolution of fitter influenza strains by modulating the host receptor-binding affinity.
authors.affiliation: Harvard-MIT Division of Health Sciences & Technology, the Koch Institute for Integrative Cancer Research, and the Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Venkataramanan
authors.initials: V
authors.lastname: Soundararajan
authors.forename: Shu
authors.initials: S
authors.lastname: Zheng
authors.forename: Neel
authors.initials: N
authors.lastname: Patel
authors.forename: Ken
authors.initials: K
authors.lastname: Warnock
authors.forename: Rahul
authors.initials: R
authors.lastname: Raman
authors.forename: Ian A
authors.initials: IA
authors.lastname: Wilson
authors.forename: S
authors.initials: S
authors.lastname: Raguram
authors.forename: V
authors.initials: V
authors.lastname: Sasisekharan
authors.forename: Ram
authors.initials: R
authors.lastname: Sasisekharan
mesh_terms: D000465:Algorithms; D000956:Antigens, Viral / Q000737:chemistry; D001665:Binding Sites; D019295:Computational Biology; D000939:Epitopes / Q000737:chemistry; D005786:Gene Expression Regulation; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D008958:Models, Molecular; D009154:Mutation; D010802:Phylogeny; D011485:Protein Binding; D017510:Protein Folding; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D011991:Receptors, Virus / Q000737:chemistry*
chemical_list: D000956:Antigens, Viral; D000939:Epitopes; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011991:Receptors, Virus