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Receptor binding by H10 influenza viruses

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Abstract

H10N8 follows H7N9 and H5N1 as the latest in a line of avian influenza viruses that cause serious disease in humans and have become a threat to public health1. Since December 2013, three human cases of H10N8 infection have been reported, two of whom are known to have died. To gather evidence relating to the epidemic potential of H10 we have determined the structure of the haemagglutinin of a previously isolated avian H10 virus and we present here results relating especially to its receptor-binding properties, as these are likely to be major determinants of virus transmissibility. Our results show, first, that the H10 virus possesses high avidity for human receptors and second, from the crystal structure of the complex formed by avian H10 haemagglutinin with human receptor, it is clear that the conformation of the bound receptor has characteristics of both the 1918 H1N1 pandemic virus2 and the human H7 viruses isolated from patients in 2013 (ref. 3). We conclude that avian H10N8 virus has sufficient avidity for human receptors to account for its infection of humans but that its preference for avian receptors should make avian-receptor-rich human airway mucins4 an effective block to widespread infection. In terms of surveillance, particular attention will be paid to the detection of mutations in the receptor-binding site of the H10 haemagglutinin that decrease its avidity for avian receptor, and could enable it to be more readily transmitted between humans.

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Figure 1: Receptor binding to H10.
Figure 2: Crystal structures of receptor complexes of H10 HA.
Figure 3: Comparison of human receptor complexes of H10 with human viruses.

Accession codes

Primary accessions

Protein Data Bank

Data deposits

Structural data have been deposited with the Protein Data Bank under accession numbers 4CYV, 4CYW, 4CYZ, 4CZ0 and 4D00.

Change history

  • 23 July 2014

    An error was corrected in the legend for Extended Data Fig. 4.

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Acknowledgements

We thank N. Bovin for gifts of sulphated sialoside. We greatly acknowledge Diamond Light Source for access to synchrotron time under proposal 7707. This work was funded by the Medical Research Council through programmes U117584222, U117570592 and U117585868.

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All authors performed experiments and contributed to the writing of the manuscript.

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

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 The structures of avian H10 HA and human H10 HA.

a, The structure of avian H10 HA trimer with one subunit coloured blue (HA1) and one coloured red (HA2), and the other two coloured grey. The locations of amino acid sequence differences between the HAs of A/mallard/Sweden/51/2002(H10N2) and A/Jiangxi-Donghu/346/2013 (H10N8) from humans are indicated by green spheres and numbered by alignment with H3 sequences. b, Receptor-binding site of human H10 HA (purple) compared to that of avian H10 HA (blue). The structure of the human H10 has been determined to 2.5 Å. Human receptors bound to avian H10 are coloured yellow (Sia-1), blue (Gal-2) and red (NAG-3), whereas the equivalents from the human H10 complex are shown in lighter shades. Potential hydrogen bonds between Arg 137 of human H10 and the human receptor are indicated by dashed lines. The arginine residue potentially also makes other hydrogen bonds (not shown) including to the glycosidic oxygen. The crystallographic asymmetric unit contains one HA trimer, the figure shows the A-chain monomer which was selected on the basis of not being involved in a close crystal contact and for having well-ordered electron density for the arginine. c, Binding of NT647-labelled human H10 to 3′-SLN (red symbols) and 6′-SLN (blue symbols). The calculated Kds were 1.81 ± 0.39 mM and 1.39 ± 0.32 mM, respectively.

Extended Data Figure 2 Biolayer interferometry measurements of binding avidity.

Biolayer interferometry binding data for A/mallard/Sweden/51/2002 (H10N2) virus (ref. 17) to sulphated 3′-SLN (purple), sulphated SLeX (green), 3′-SLN (red), SLeX (orange) and 6′-SLN (blue).

Extended Data Figure 3 Structural comparison of the H10 and H5 HA binding sites.

A comparison of the receptor-binding sites of H10 (a) and H5 (b) (ref. 20) HAs from complexes formed between the HAs and sulphated 3′-SLN. Electron density (2Fc – Fo, 0.8σ) for the receptor is shown in a. In H10 HA the sulphate group approaches Lys 158A, the first inserted residue in the 150-loop. By contrast, in H5 HA the sulphate approaches Lys 193 in the 190-helix (b) (the equivalent residue in H10 HA is aspartic acid).

Extended Data Figure 4 Comparison of H10 and H1 HA in complex with avian and human receptors.

Comparisons of avian- and human-receptor-bound forms of H10 (a) and H1 (b) HAs. The arrows indicate the upward movement of Gln 226 in the complexes formed with avian receptor.

Extended Data Table 1 Table of crystallographic statistics for the structure determined

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Vachieri, S., Xiong, X., Collins, P. et al. Receptor binding by H10 influenza viruses. Nature 511, 475–477 (2014). https://doi.org/10.1038/nature13443

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