Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Receptor binding by an H7N9 influenza virus from humans

Nature volume 499, pages 496–499 (2013)Cite this article

Subjects

Abstract

Of the 132 people known to have been infected with H7N9 influenza viruses in China, 37 died, and many were severely ill1. Infection seems to have involved contact with infected poultry2,3. We have examined the receptor-binding properties of this H7N9 virus and compared them with those of an avian H7N3 virus. We find that the human H7 virus has significantly higher affinity for α-2,6-linked sialic acid analogues (‘human receptor’) than avian H7 while retaining the strong binding to α-2,3-linked sialic acid analogues (‘avian receptor’) characteristic of avian viruses. The human H7 virus does not, therefore, have the preference for human versus avian receptors characteristic of pandemic viruses. X-ray crystallography of the receptor-binding protein, haemagglutinin (HA), in complex with receptor analogues indicates that both human and avian receptors adopt different conformations when bound to human H7 HA than they do when bound to avian H7 HA. Human receptor bound to human H7 HA exits the binding site in a different direction to that seen in complexes formed by HAs from pandemic viruses4,5 and from an aerosol-transmissible H5 mutant6. The human-receptor-binding properties of human H7 probably arise from the introduction of two bulky hydrophobic residues by the substitutions Gln226Leu and Gly186Val. The former is shared with the 1957 H2 and 1968 H3 pandemic viruses and with the aerosol-transmissible H5 mutant. We conclude that the human H7 virus has acquired some of the receptor-binding characteristics that are typical of pandemic viruses, but its retained preference for avian receptor may restrict its further evolution towards a virus that could transmit efficiently between humans, perhaps by binding to avian-receptor-rich mucins in the human respiratory tract7 rather than to cellular receptors.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Virus binding to human and avian receptors.
Figure 2: Crystal structures of human receptor bound to human and avian HA.
Figure 3: Crystal structures of avian receptor bound to human and avian HA.

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

Data deposits

Structural data have been deposited with the Protein DataBank with accession codes: 4BSA, 4BSB, 4BSC, 4BSD, 4BSE, 4BSF, 4BSG, 4BSH and 4BSI.

References

  1. World Health Organization. Number of confirmed human cases of avian influenza A(H7N9) reported to WHO Report 8 - data in WHO/HQ as of 30 May 2013, 15:45 GMT+1. http://www.who.int/influenza/human_animal_interface/influenza_h7n9/08_ReportWebH7N9Number.pdf (2013)

  2. Chen, Y. et al. Human infections with the emerging avian influenza A H7N9 virus from wet market poultry: clinical analysis and characterisation of viral genome. Lancet 381, 1916–1925 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Gao, R. et al. Human infection with a novel avian-origin influenza A (H7N9) virus. N. Engl. J. Med. 368, 1888–1897 (2013)

    Article  CAS  PubMed  Google Scholar 

  4. Eisen, M. B., Sabesan, S., Skehel, J. J. & Wiley, D. C. 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)

    Article  CAS  PubMed  Google Scholar 

  5. Liu, J. 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)

    Article  CAS  ADS  PubMed  PubMed Central  Google Scholar 

  6. Xiong, X. et al. Receptor binding by a ferret-transmissible H5 avian influenza virus. Nature 497, 392–396 (2013)

    Article  CAS  ADS  PubMed  Google Scholar 

  7. Couceiro, J. N., Paulson, J. C. & Baum, L. G. 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)

    Article  CAS  PubMed  Google Scholar 

  8. Kageyama, T. et al. Genetic analysis of novel avian A(H7N9) influenza viruses isolated from patients in China, February to April 2013. Eurosurveillance 18, 20453 (2013)

    CAS  PubMed  Google Scholar 

  9. Butt, K. M. et al. Human infection with an avian H9N2 influenza A virus in Hong Kong in 2003. J. Clin. Microbiol. 43, 5760–5767 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lin, Y. P. et al. Avian-to-human transmission of H9N2 subtype influenza A viruses: relationship between H9N2 and H5N1 human isolates. Proc. Natl Acad. Sci. USA 97, 9654–9658 (2000)

    Article  CAS  ADS  PubMed  PubMed Central  Google Scholar 

  11. Peiris, M. et al. Human infection with influenza H9N2. Lancet 354, 916–917 (1999)

    Article  CAS  PubMed  Google Scholar 

  12. Russell, R. J., Stevens, D. J., Haire, L. F., Gamblin, S. J. & Skehel, J. J. Avian and human receptor binding by hemagglutinins of influenza A viruses. Glycoconj. J. 23, 85–92 (2006)

    Article  CAS  PubMed  Google Scholar 

  13. Ha, Y., Stevens, D. J., Skehel, J. J. & Wiley, D. C. 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)

    Article  CAS  ADS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  ADS  PubMed  Google Scholar 

  16. Russell, R. J. et al. H1 and H7 influenza haemagglutinin structures extend a structural classification of haemagglutinin subtypes. Virology 325, 287–296 (2004)

    Article  CAS  PubMed  Google Scholar 

  17. Zhang, W. et al. An airborne transmissible avian influenza H5 hemagglutinin seen at the atomic level. Science http://dx.doi.org/10.1126/science.1236787 (2 May 2013)

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

    Article  CAS  PubMed  Google Scholar 

  19. Wagner, R., Matrosovich, M. & Klenk, H. D. Functional balance between haemagglutinin and neuraminidase in influenza virus infections. Rev. Med. Virol. 12, 159–166 (2002)

    Article  PubMed  Google Scholar 

  20. Garten, W. & Klenk, H. D. Understanding influenza virus pathogenicity. Trends Microbiol. 7, 99–100 (1999)

    Article  CAS  PubMed  Google Scholar 

  21. Skehel, J. J. & Wiley, D. C. Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. Annu. Rev. Biochem. 69, 531–569 (2000)

    Article  CAS  PubMed  Google Scholar 

  22. Steinhauer, D. A. Role of hemagglutinin cleavage for the pathogenicity of influenza virus. Virology 258, 1–20 (1999)

    Article  CAS  PubMed  Google Scholar 

  23. Daniels, R. S. et al. Fusion mutants of the influenza virus hemagglutinin glycoprotein. Cell 40, 431–439 (1985)

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  25. Imai, M. 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)

    Article  CAS  ADS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  ADS  PubMed  PubMed Central  Google Scholar 

  27. Emsley, P. & Cowtan, K. Coot: model-building tools for molecular graphics. Acta Crystallogr. D 60, 2126–2132 (2004)

    Article  PubMed  Google Scholar 

  28. Collaborative Computational Project, number 4. The CCP4 suite: programs for protein crystallography. Acta Crystallogr. D 50, 760–763 (1994)

  29. Skehel, J. J. & Schild, G. C. The polypeptide composition of influenza A viruses. Virology 44, 396–408 (1971)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge Y. Shu for sharing information and samples on recent H7N9 virus infections. We are grateful to staff at the Diamond Light Source Synchrotron for assistance and beamline access under proposal 7707 and the staff of the NIMR Large Scale laboratory. This work was funded by the Medical Research Council through programmes U117584222, U117570592, U117585868 and U117512723.

Author information

Authors and Affiliations

  1. MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW71AA, UK,

    Xiaoli Xiong, Stephen R. Martin, Lesley F. Haire, Patrick J. Collins, Philip A. Walker, John J. Skehel & Steven J. Gamblin

  2. WHO Collaborating Centre for Reference and Research on Influenza, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW71AA, UK,

    Stephen A. Wharton, Rodney S. Daniels, Michael S. Bennett & John W. McCauley

Authors
  1. Xiaoli Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephen R. Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lesley F. Haire
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stephen A. Wharton
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rodney S. Daniels
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael S. Bennett
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. John W. McCauley
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Patrick J. Collins
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Philip A. Walker
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. John J. Skehel
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Steven J. Gamblin
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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

Corresponding authors

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

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1–6 and Supplementary Tables 1–3. (PDF 2218 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xiong, X., Martin, S., Haire, L. et al. Receptor binding by an H7N9 influenza virus from humans. Nature 499, 496–499 (2013). https://doi.org/10.1038/nature12372

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature12372

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing