Characterization of changes in the hemagglutinin that accompanied the emergence of H3N2/1968 pandemic influenza viruses

Johanna West; Juliane Roder; Tatyana Matrosovich; Jana Beicht; Jan Baumann; Nancy Mounogou Kouassi; Jennifer Doedt; Nicolai Bovin; Gianpiero Zamperin; Michele Gastaldelli; Annalisa Salviato; Francesco Bonfante; Sergei Kosakovsky Pond; Sander Herfst; Ron Fouchier; Jochen Wilhelm; Hans Dieter Klenk; Mikhail Matrosovich

doi:10.1371/journal.ppat.1009566

Characterization of changes in the hemagglutinin that accompanied the emergence of H3N2/1968 pandemic influenza viruses

Johanna West, Juliane Roder, Tatyana Matrosovich, Jana Beicht, Jan Baumann, Nancy Mounogou Kouassi, Jennifer Doedt, Nicolai Bovin, Gianpiero Zamperin, Michele Gastaldelli, Annalisa Salviato, Francesco Bonfante, Sergei Kosakovsky Pond, Sander Herfst, Ron Fouchier, Jochen Wilhelm, Hans Dieter Klenk, Mikhail Matrosovich^*

^*Corresponding author for this work

Virology

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Abstract

The hemagglutinin (HA) of A/H3N2 pandemic influenza viruses (IAVs) of 1968 differed from its inferred avian precursor by eight amino acid substitutions. To determine their phenotypic effects, we studied recombinant variants of A/Hong Kong/1/1968 virus containing either human-type or avian-type amino acids in the corresponding positions of HA. The precursor HA displayed receptor binding profile and high conformational stability typical for duck IAVs. Substitutions Q226L and G228S, in addition to their known effects on receptor specificity and replication, marginally decreased HA stability. Substitutions R62I, D63N, D81N and N193S reduced HA binding avidity. Substitutions R62I, D81N and A144G promoted viral replication in human airway epithelial cultures. Analysis of HA sequences revealed that substitutions D63N and D81N accompanied by the addition of N-glycans represent common markers of avian H3 HA adaptation to mammals. Our results advance understanding of genotypic and phenotypic changes in IAV HA required for avian-to-human adaptation and pandemic emergence.

Original language	English
Article number	e1009566
Journal	PLoS Pathogens
Volume	17
Issue number	9
DOIs	https://doi.org/10.1371/journal.ppat.1009566
Publication status	Published - Sept 2021

Bibliographical note

Funding Information:
This work was supported by the European Union's Seventh Framework Programme for Research, Technological Development, and Demonstration under grant agreement 278433 - PREDEMICS (Mikhail Matrosovich); by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - Project numbers 197785619 - SFB 1021 (Mikhail Matrosovich) and 284237345 - KF0309/Z1 (Jochen Wilhelm); by an NWO VIDI grant (contract number 91715372) (Sander Herfst); and by NIH/NIAID contract HHSN272201400008C (Ron Fouchier). Johanna West was supported by a fellowship from the J?rgen Manchot Stiftung, D?sseldorf, Germany. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2021 West et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Characterization of changes in the hemagglutinin that accompanied the emergence of H3N2 1968 pandemic influenza virusesFinal published version, 3.26 MBLicence: CC BY

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West, J., Roder, J., Matrosovich, T., Beicht, J., Baumann, J., Kouassi, N. M., Doedt, J., Bovin, N., Zamperin, G., Gastaldelli, M., Salviato, A., Bonfante, F., Pond, S. K., Herfst, S., Fouchier, R., Wilhelm, J., Klenk, H. D., & Matrosovich, M. (2021). Characterization of changes in the hemagglutinin that accompanied the emergence of H3N2/1968 pandemic influenza viruses. PLoS Pathogens, 17(9), Article e1009566. https://doi.org/10.1371/journal.ppat.1009566

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title = "Characterization of changes in the hemagglutinin that accompanied the emergence of H3N2/1968 pandemic influenza viruses",

abstract = "The hemagglutinin (HA) of A/H3N2 pandemic influenza viruses (IAVs) of 1968 differed from its inferred avian precursor by eight amino acid substitutions. To determine their phenotypic effects, we studied recombinant variants of A/Hong Kong/1/1968 virus containing either human-type or avian-type amino acids in the corresponding positions of HA. The precursor HA displayed receptor binding profile and high conformational stability typical for duck IAVs. Substitutions Q226L and G228S, in addition to their known effects on receptor specificity and replication, marginally decreased HA stability. Substitutions R62I, D63N, D81N and N193S reduced HA binding avidity. Substitutions R62I, D81N and A144G promoted viral replication in human airway epithelial cultures. Analysis of HA sequences revealed that substitutions D63N and D81N accompanied by the addition of N-glycans represent common markers of avian H3 HA adaptation to mammals. Our results advance understanding of genotypic and phenotypic changes in IAV HA required for avian-to-human adaptation and pandemic emergence.",

author = "Johanna West and Juliane Roder and Tatyana Matrosovich and Jana Beicht and Jan Baumann and Kouassi, {Nancy Mounogou} and Jennifer Doedt and Nicolai Bovin and Gianpiero Zamperin and Michele Gastaldelli and Annalisa Salviato and Francesco Bonfante and Pond, {Sergei Kosakovsky} and Sander Herfst and Ron Fouchier and Jochen Wilhelm and Klenk, {Hans Dieter} and Mikhail Matrosovich",

note = "Funding Information: This work was supported by the European Union's Seventh Framework Programme for Research, Technological Development, and Demonstration under grant agreement 278433 - PREDEMICS (Mikhail Matrosovich); by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - Project numbers 197785619 - SFB 1021 (Mikhail Matrosovich) and 284237345 - KF0309/Z1 (Jochen Wilhelm); by an NWO VIDI grant (contract number 91715372) (Sander Herfst); and by NIH/NIAID contract HHSN272201400008C (Ron Fouchier). Johanna West was supported by a fellowship from the J?rgen Manchot Stiftung, D?sseldorf, Germany. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2021 West et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

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West, J, Roder, J, Matrosovich, T, Beicht, J, Baumann, J, Kouassi, NM, Doedt, J, Bovin, N, Zamperin, G, Gastaldelli, M, Salviato, A, Bonfante, F, Pond, SK, Herfst, S , Fouchier, R, Wilhelm, J, Klenk, HD & Matrosovich, M 2021, 'Characterization of changes in the hemagglutinin that accompanied the emergence of H3N2/1968 pandemic influenza viruses', PLoS Pathogens, vol. 17, no. 9, e1009566. https://doi.org/10.1371/journal.ppat.1009566

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AU - West, Johanna

AU - Roder, Juliane

AU - Matrosovich, Tatyana

AU - Beicht, Jana

AU - Baumann, Jan

AU - Kouassi, Nancy Mounogou

AU - Doedt, Jennifer

AU - Bovin, Nicolai

AU - Zamperin, Gianpiero

AU - Gastaldelli, Michele

AU - Salviato, Annalisa

AU - Bonfante, Francesco

AU - Pond, Sergei Kosakovsky

AU - Herfst, Sander

AU - Fouchier, Ron

AU - Wilhelm, Jochen

AU - Klenk, Hans Dieter

AU - Matrosovich, Mikhail

N1 - Funding Information: This work was supported by the European Union's Seventh Framework Programme for Research, Technological Development, and Demonstration under grant agreement 278433 - PREDEMICS (Mikhail Matrosovich); by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - Project numbers 197785619 - SFB 1021 (Mikhail Matrosovich) and 284237345 - KF0309/Z1 (Jochen Wilhelm); by an NWO VIDI grant (contract number 91715372) (Sander Herfst); and by NIH/NIAID contract HHSN272201400008C (Ron Fouchier). Johanna West was supported by a fellowship from the J?rgen Manchot Stiftung, D?sseldorf, Germany. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2021 West et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2021/9

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N2 - The hemagglutinin (HA) of A/H3N2 pandemic influenza viruses (IAVs) of 1968 differed from its inferred avian precursor by eight amino acid substitutions. To determine their phenotypic effects, we studied recombinant variants of A/Hong Kong/1/1968 virus containing either human-type or avian-type amino acids in the corresponding positions of HA. The precursor HA displayed receptor binding profile and high conformational stability typical for duck IAVs. Substitutions Q226L and G228S, in addition to their known effects on receptor specificity and replication, marginally decreased HA stability. Substitutions R62I, D63N, D81N and N193S reduced HA binding avidity. Substitutions R62I, D81N and A144G promoted viral replication in human airway epithelial cultures. Analysis of HA sequences revealed that substitutions D63N and D81N accompanied by the addition of N-glycans represent common markers of avian H3 HA adaptation to mammals. Our results advance understanding of genotypic and phenotypic changes in IAV HA required for avian-to-human adaptation and pandemic emergence.

AB - The hemagglutinin (HA) of A/H3N2 pandemic influenza viruses (IAVs) of 1968 differed from its inferred avian precursor by eight amino acid substitutions. To determine their phenotypic effects, we studied recombinant variants of A/Hong Kong/1/1968 virus containing either human-type or avian-type amino acids in the corresponding positions of HA. The precursor HA displayed receptor binding profile and high conformational stability typical for duck IAVs. Substitutions Q226L and G228S, in addition to their known effects on receptor specificity and replication, marginally decreased HA stability. Substitutions R62I, D63N, D81N and N193S reduced HA binding avidity. Substitutions R62I, D81N and A144G promoted viral replication in human airway epithelial cultures. Analysis of HA sequences revealed that substitutions D63N and D81N accompanied by the addition of N-glycans represent common markers of avian H3 HA adaptation to mammals. Our results advance understanding of genotypic and phenotypic changes in IAV HA required for avian-to-human adaptation and pandemic emergence.

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Characterization of changes in the hemagglutinin that accompanied the emergence of H3N2/1968 pandemic influenza viruses

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