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Epistasis mediates the evolution of the receptor binding mode in recent human H3N2 hemagglutinin

New publication in Nature Communications from Roberto Bruzzone and Weiwen Liang examining the evolution of the receptor binding mode of the hemagglutinin (HA) protein in recent human H3N2 influenza virus.


The study uses X-ray crystallography, glycan binding analyses, and mutagenesis experiments to show that two mutations, G186D and D190N, have coevolved in the HA and coordinately drive changes in the receptor binding mode. They also find that this evolution of the receptor binding mode is accompanied by changes in antigenicity and compatibility with an egg-adaptive mutation commonly found in seasonal influenza vaccines. Overall, the work elucidates the role of epistasis in shaping the recent evolution of the H3N2 HA and highlights the high evolvability of its receptor binding properties.

 

Abstract

The receptor-binding site of influenza A virus hemagglutinin partially overlaps with major antigenic sites and constantly evolves. In this study, we observe that mutations G186D and D190N in the hemagglutinin receptor-binding site have coevolved in two recent human H3N2 clades. X-ray crystallography results show that these mutations coordinately drive the evolution of the hemagglutinin receptor binding mode. Epistasis between G186D and D190N is further demonstrated by glycan binding and thermostability analyses. Immunization and neutralization experiments using mouse and human samples indicate that the evolution of receptor binding mode is accompanied by a change in antigenicity. Besides, combinatorial mutagenesis reveals that G186D and D190N, along with other natural mutations in recent H3N2 strains, alter the compatibility with a common egg-adaptive mutation in seasonal influenza vaccines. Overall, our findings elucidate the role of epistasis in shaping the recent evolution of human H3N2 hemagglutinin and substantiate the high evolvability of its receptor-binding mode.







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