Letter | Published:

Receptor binding by a ferret-transmissible H5 avian influenza virus

Nature volume 497, pages 392396 (16 May 2013) | Download Citation

Abstract

Cell-surface-receptor binding by influenza viruses is a key determinant of their transmissibility, both from avian and animal species to humans as well as from human to human. Highly pathogenic avian H5N1 viruses that are a threat to public health have been observed to acquire affinity for human receptors, and transmissible-mutant-selection experiments have identified a virus that is transmissible in ferrets1,2,3, the generally accepted experimental model for influenza in humans. Here, our quantitative biophysical measurements of the receptor-binding properties of haemagglutinin (HA) from the transmissible mutant indicate a small increase in affinity for human receptor and a marked decrease in affinity for avian receptor. From analysis of virus and HA binding data we have derived an algorithm that predicts virus avidity from the affinity of individual HA–receptor interactions. It reveals that the transmissible-mutant virus has a 200-fold preference for binding human over avian receptors. The crystal structure of the transmissible-mutant HA in complex with receptor analogues shows that it has acquired the ability to bind human receptor in the same folded-back conformation as seen for HA from the 1918, 1957 (ref. 4), 1968 (ref. 5) and 2009 (ref. 6) pandemic viruses. This binding mode is substantially different from that by which non-transmissible wild-type H5 virus HA binds human receptor. The structure of the complex also explains how the change in preference from avian to human receptors arises from the Gln226Leu substitution, which facilitates binding to human receptor but restricts binding to avian receptor. Both features probably contribute to the acquisition of transmissibility by this mutant virus.

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Data deposits

Structural data have been deposited with the Protein Data Bank under accession codes 4BGW, 4BGX, 4BGY, 4BGZ, 4BH0, 4BH1, 4BH2, 4BH3 and 4BH4.

References

  1. 1.

    et al. Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature 486, 420–428 (2012)

  2. 2.

    et al. Airborne transmission of influenza A/H5N1 virus between ferrets. Science 336, 1534–1541 (2012)

  3. 3.

    et al. In vitro evolution of H5N1 avian influenza virus toward human-type receptor specificity. Virology 422, 105–113 (2012)

  4. 4.

    et al. Structures of receptor complexes formed by hemagglutinins from the Asian Influenza pandemic of 1957. Proc. Natl Acad. Sci. USA 106, 17175–17180 (2009)

  5. 5.

    , , & Binding of the influenza A virus to cell-surface receptors: structures of five hemagglutinin–sialyloligosaccharide complexes determined by X-ray crystallography. Virology 232, 19–31 (1997)

  6. 6.

    , , , & Structural characterization of the hemagglutinin receptor specificity from the 2009 H1N1 influenza pandemic. J. Virol. 86, 982–990 (2012)

  7. 7.

    et al. Growth of H5N1 influenza A viruses in the upper respiratory tracts of mice. PLoS Pathog. 3, e133 (2007)

  8. 8.

    , , & Receptor specificity in human, avian, and equine H2 and H3 influenza virus isolates. Virology 205, 17–23 (1994)

  9. 9.

    et al. Early alterations of the receptor-binding properties of H1, H2, and H3 avian influenza virus hemagglutinins after their introduction into mammals. J. Virol. 74, 8502–8512 (2000)

  10. 10.

    , & Influenza virus strains selectively recognize sialyloligosaccharides on human respiratory epithelium; the role of the host cell in selection of hemagglutinin receptor specificity. Virus Res. 29, 155–165 (1993)

  11. 11.

    et al. Avian flu: influenza virus receptors in the human airway. Nature 440, 435–436 (2006)

  12. 12.

    , , & Structural organization of a filamentous influenza A virus. Proc. Natl Acad. Sci. USA 107, 10685–10690 (2010)

  13. 13.

    et al. Hemagglutinins from two influenza virus variants bind to sialic acid derivatives with millimolar dissociation constants: a 500-MHz proton nuclear magnetic resonance study. Biochemistry 28, 8388–8396 (1989)

  14. 14.

    et al. Specification of receptor-binding phenotypes of influenza virus isolates from different hosts using synthetic sialylglycopolymers: non-egg-adapted human H1 and H3 influenza A and influenza B viruses share a common high binding affinity for 6′-sialyl(N-acetyllactosamine). Virology 232, 345–350 (1997)

  15. 15.

    & Natural and synthetic sialic acid-containing inhibitors of influenza virus receptor binding. Rev. Med. Virol. 13, 85–97 (2003)

  16. 16.

    , , & X-ray structures of H5 avian and H9 swine influenza virus hemagglutinins bound to avian and human receptor analogs. Proc. Natl Acad. Sci. USA 98, 11181–11186 (2001)

  17. 17.

    , , & X-ray structure of the hemagglutinin of a potential H3 avian progenitor of the 1968 Hong Kong pandemic influenza virus. Virology 309, 209–218 (2003)

  18. 18.

    et al. Glycosylation at 158N of the hemagglutinin protein and receptor binding specificity synergistically affect the antigenicity and immunogenicity of a live attenuated H5N1 A/Vietnam/1203/2004 vaccine virus in ferrets. J. Virol. 84, 6570–6577 (2010)

  19. 19.

    et al. Haemagglutinin mutations responsible for the binding of H5N1 influenza A viruses to human-type receptors. Nature 444, 378–382 (2006)

  20. 20.

    & Dynamics of glycoprotein charge in the evolutionary history of human influenza. PLoS ONE 5, e15674 (2010)

  21. 21.

    et al. Evolution of the receptor binding properties of the influenza A(H3N2) haemagglutinin. Proc. Natl Acad. Sci. USA Nature. 109, 21474–21479 (2012)

  22. 22.

    et al. Conformational changes in the hemagglutinin of influenza virus which accompany heat-induced fusion of virus with liposomes. Virology 155, 484–497 (1986)

  23. 23.

    et al. Studies using double mutants of the conformational transitions in influenza hemagglutinin required for its membrane fusion activity. Proc. Natl Acad. Sci. USA 93, 12873–12878 (1996)

  24. 24.

    et al. The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science 303, 1838–1842 (2004)

  25. 25.

    et al. Glycan microarray analysis of the hemagglutinins from modern and pandemic influenza viruses reveals different receptor specificities. J. Mol. Biol. 355, 1143–1155 (2006)

  26. 26.

    et al. Host-mediated selection of influenza virus receptor variants. Sialic acid-α2,6Gal-specific clones of A/duck/Ukraine/1/63 revert to sialic acid-α2,3Gal-specific wild type in ovo. J. Biol. Chem. 260, 7362–7367 (1985)

  27. 27.

    et al. Single amino acid substitutions in influenza haemagglutinin change receptor binding specificity. Nature 304, 76–78 (1983)

  28. 28.

    et al. Receptor specificity and transmission of H2N2 subtype viruses isolated from the pandemic of 1957. PLoS ONE 5, e11158 (2010)

  29. 29.

    et al. Receptor-binding profiles of H7 subtype influenza viruses in different host species. J. Virol. 86, 4370–4379 (2012)

  30. 30.

    & Influenza type A in humans, mammals and birds: determinants of virus virulence, host-range and interspecies transmission. BioEssays 25, 657–671 (2003)

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Acknowledgements

We are grateful to staff at the Diamond Light Source Synchrotron for assistance and beamline access under proposal 7707, E. Christodoulou and S. Vachieri for discussions on protein expression, the staff of the NIMR Large Scale Laboratory, L Haire for assistance with crystallization experiments and S. Smerdon and P. Rosenthal for discussions. H.X. was supported by BBSRC (award number BB/E010806). This work was funded by the Medical Research Council through programmes U117584222, U117512723 and U117570592.

Author information

Author notes

    • Xiaoli Xiong
    • , Peter J. Coombs
    •  & Stephen R. Martin

    These authors contributed equally to this work.

    • Haixia Xiao

    Present address: Laboratory of Protein Engineering and Vaccines, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China.

Affiliations

  1. MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK

    • Xiaoli Xiong
    • , Peter J. Coombs
    • , Stephen R. Martin
    • , Haixia Xiao
    • , John W. McCauley
    • , Philip A. Walker
    • , Patrick J. Collins
    • , John J. Skehel
    •  & Steven J. Gamblin
  2. Ministry of Agriculture, Key Laboratory of Plant Pathology, China Agricultural University, Yuanmingyuanxilu, 2, Beijing 100193, China

    • Junfeng Liu
  3. Novartis Institutes for BioMedical Research, Klybeckstrasse 141, CH-4057 Basel, Switzerland

    • Kathrin Locher
  4. Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA

    • Yoshihiro Kawaoka

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Contributions

X.X., P.J.C., S.R.M., J.L., H.X., J.W.M., K.L., P.A.W., P.C., Y.K., J.J.S. and S.J.G. all performed experiments and contributed to the writing of the manuscript.

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The authors declare no competing financial interests.

Corresponding authors

Correspondence to John J. Skehel or Steven J. Gamblin.

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    Supplementary Information

    This file contains Supplementary Figures 1 and 2A-I with additional Supplementary Text and Data and Supplementary Tables 1, 1B, 2a, 2b and additional references.

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DOI

https://doi.org/10.1038/nature12144

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