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Title: Three mutations switch H7N9 influenza to human-type receptor specificity

Abstract

The avian H7N9 influenza outbreak in 2013 resulted from an unprecedented incidence of influenza transmission to humans from infected poultry. The majority of human H7N9 isolates contained a hemagglutinin (HA) mutation (Q226L) that has previously been associated with a switch in receptor specificity from avian-type (NeuAcα2-3Gal) to human-type (NeuAcα2-6Gal), as documented for the avian progenitors of the 1957 (H2N2) and 1968 (H3N2) human influenza pandemic viruses. While this raised concern that the H7N9 virus was adapting to humans, the mutation was not sufficient to switch the receptor specificity of H7N9, and has not resulted in sustained transmission in humans. To determine if the H7 HA was capable of acquiring human-type receptor specificity, we conducted mutation analyses. Remarkably, three amino acid mutations conferred a switch in specificity for human-type receptors that resembled the specificity of the 2009 human H1 pandemic virus, and promoted binding to human trachea epithelial cells.

Authors:
; ORCiD logo; ; ; ; ; ; ; ; ORCiD logo; ; ORCiD logo; ; ; ORCiD logo; ; ORCiD logo;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NIHOTHER
OSTI Identifier:
1400283
Resource Type:
Journal Article
Resource Relation:
Journal Name: PLoS Pathogens; Journal Volume: 13; Journal Issue: 6
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

de Vries, Robert P., Peng, Wenjie, Grant, Oliver C., Thompson, Andrew J., Zhu, Xueyong, Bouwman, Kim M., de la Pena, Alba T. Torrents, van Breemen, Marielle J., Ambepitiya Wickramasinghe, Iresha N., de Haan, Cornelis A. M., Yu, Wenli, McBride, Ryan, Sanders, Rogier W., Woods, Robert J., Verheije, Monique H., Wilson, Ian A., Paulson, James C., and Fernandez-Sesma, Ana. Three mutations switch H7N9 influenza to human-type receptor specificity. United States: N. p., 2017. Web. doi:10.1371/journal.ppat.1006390.
de Vries, Robert P., Peng, Wenjie, Grant, Oliver C., Thompson, Andrew J., Zhu, Xueyong, Bouwman, Kim M., de la Pena, Alba T. Torrents, van Breemen, Marielle J., Ambepitiya Wickramasinghe, Iresha N., de Haan, Cornelis A. M., Yu, Wenli, McBride, Ryan, Sanders, Rogier W., Woods, Robert J., Verheije, Monique H., Wilson, Ian A., Paulson, James C., & Fernandez-Sesma, Ana. Three mutations switch H7N9 influenza to human-type receptor specificity. United States. doi:10.1371/journal.ppat.1006390.
de Vries, Robert P., Peng, Wenjie, Grant, Oliver C., Thompson, Andrew J., Zhu, Xueyong, Bouwman, Kim M., de la Pena, Alba T. Torrents, van Breemen, Marielle J., Ambepitiya Wickramasinghe, Iresha N., de Haan, Cornelis A. M., Yu, Wenli, McBride, Ryan, Sanders, Rogier W., Woods, Robert J., Verheije, Monique H., Wilson, Ian A., Paulson, James C., and Fernandez-Sesma, Ana. Thu . "Three mutations switch H7N9 influenza to human-type receptor specificity". United States. doi:10.1371/journal.ppat.1006390.
@article{osti_1400283,
title = {Three mutations switch H7N9 influenza to human-type receptor specificity},
author = {de Vries, Robert P. and Peng, Wenjie and Grant, Oliver C. and Thompson, Andrew J. and Zhu, Xueyong and Bouwman, Kim M. and de la Pena, Alba T. Torrents and van Breemen, Marielle J. and Ambepitiya Wickramasinghe, Iresha N. and de Haan, Cornelis A. M. and Yu, Wenli and McBride, Ryan and Sanders, Rogier W. and Woods, Robert J. and Verheije, Monique H. and Wilson, Ian A. and Paulson, James C. and Fernandez-Sesma, Ana},
abstractNote = {The avian H7N9 influenza outbreak in 2013 resulted from an unprecedented incidence of influenza transmission to humans from infected poultry. The majority of human H7N9 isolates contained a hemagglutinin (HA) mutation (Q226L) that has previously been associated with a switch in receptor specificity from avian-type (NeuAcα2-3Gal) to human-type (NeuAcα2-6Gal), as documented for the avian progenitors of the 1957 (H2N2) and 1968 (H3N2) human influenza pandemic viruses. While this raised concern that the H7N9 virus was adapting to humans, the mutation was not sufficient to switch the receptor specificity of H7N9, and has not resulted in sustained transmission in humans. To determine if the H7 HA was capable of acquiring human-type receptor specificity, we conducted mutation analyses. Remarkably, three amino acid mutations conferred a switch in specificity for human-type receptors that resembled the specificity of the 2009 human H1 pandemic virus, and promoted binding to human trachea epithelial cells.},
doi = {10.1371/journal.ppat.1006390},
journal = {PLoS Pathogens},
number = 6,
volume = 13,
place = {United States},
year = {Thu Jun 15 00:00:00 EDT 2017},
month = {Thu Jun 15 00:00:00 EDT 2017}
}
  • Glycan chains that terminate in sialic acid (Neu5Ac) are frequently the receptors targeted by pathogens for initial adhesion. Carbohydrate-binding proteins (lectins) with specificity for Neu5Ac are particularly useful in the detection and isolation of sialylated glycoconjugates, such as those associated with pathogen adhesion as well as those characteristic of several diseases including cancer. Structural studies of lectins are essential in order to understand the origin of their specificity, which is particularly important when employing such reagents as diagnostic tools. Here, we report a crystallographic and molecular dynamics (MD) analysis of a lectin from Polyporus squamosus (PSL) that is specific formore » glycans terminating with the sequence Neu5Ac{alpha}2-6Gal{beta}. Because of its importance as a histological reagent, the PSL structure was solved (to 1.7 {angstrom}) in complex with a trisaccharide, whose sequence (Neu5Ac{alpha}2-6Gal{beta}1-4GlcNAc) is exploited by influenza A hemagglutinin for viral adhesion to human tissue. The structural data illuminate the origin of the high specificity of PSL for the Neu5Ac{alpha}2-6Gal sequence. Theoretical binding free energies derived from the MD data confirm the key interactions identified crystallographically and provide additional insight into the relative contributions from each amino acid, as well as estimates of the importance of entropic and enthalpic contributions to binding.« less
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  • Influenza virus hemagglutinin (HA) is the viral envelope protein that mediates viral attachment to host cells and elicits membrane fusion. The HA receptor-binding specificity is a key determinant for the host range and transmissibility of influenza viruses. In human pandemics of the 20th century, the HA normally has acquired specificity for human-like receptors before widespread infection. Crystal structures of the H1 HA from the 2009 human pandemic (A/California/04/2009 [CA04]) in complex with human and avian receptor analogs reveal conserved recognition of the terminal sialic acid of the glycan ligands. However, favorable interactions beyond the sialic acid are found only formore » {alpha}2-6-linked glycans and are mediated by Asp190 and Asp225, which hydrogen bond with Gal-2 and GlcNAc-3. For {alpha}2-3-linked glycan receptors, no specific interactions beyond the terminal sialic acid are observed. Our structural and glycan microarray analyses, in the context of other high-resolution HA structures with {alpha}2-6- and {alpha}2-3-linked glycans, now elucidate the structural basis of receptor-binding specificity for H1 HAs in human and avian viruses and provide a structural explanation for the preference for {alpha}2-6 siaylated glycan receptors for the 2009 pandemic swine flu virus.« less