Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Dec 6;342(6163):1230-5.
doi: 10.1126/science.1243761.

Preferential recognition of avian-like receptors in human influenza A H7N9 viruses

Rui Xu  1 , Robert P de Vries, Xueyong Zhu, Corwin M Nycholat, Ryan McBride, Wenli Yu, James C Paulson, Ian A Wilson
Affiliations

Preferential recognition of avian-like receptors in human influenza A H7N9 viruses

Rui Xu et al. Science. .

Abstract

The 2013 outbreak of avian-origin H7N9 influenza in eastern China has raised concerns about its ability to transmit in the human population. The hemagglutinin glycoprotein of most human H7N9 viruses carries Leu(226), a residue linked to adaptation of H2N2 and H3N2 pandemic viruses to human receptors. However, glycan array analysis of the H7 hemagglutinin reveals negligible binding to humanlike α2-6-linked receptors and strong preference for a subset of avian-like α2-3-linked glycans recognized by all avian H7 viruses. Crystal structures of H7N9 hemagglutinin and six hemagglutinin-glycan complexes have elucidated the structural basis for preferential recognition of avian-like receptors. These findings suggest that the current human H7N9 viruses are poorly adapted for efficient human-to-human transmission.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1
Crystal structure of the HA from a human H7N9 virus (A/Shanghai/2/2013, Sh2). (A) HA trimer is shown in cartoon representation. For one of the protomers, HA1 is colored in green and HA2 in cyan. The other two protomers (B and C) of the trimer are in yellow and magenta respectively. N-glycosylation sites and N-linked glycans are highlighted in sticks and numbered at the Asn attachment site. (B) Human H7 HA has Leu226 in its receptor-binding site. (C) Variation at the four HA positions that are known to mediate the switch in receptor binding specificity for human H1, H2 and H3 pandemic viruses and the corresponding sequences in H1, H2, H3 and H5 subtypes in avian viruses in comparison with human H7N9.
Fig. 2
Fig. 2
Receptor binding specificity of H7N9 HAs determined by plate-based glycan binding and glycan microarray analyses. (A) ELISA plates coated with either α2-3 or α2-6 linked SLNLN-PAA were probed with recombinant HAs produced in human kidney (HEK293S GnTI-) cells. The HAs were human H1N1 seasonal strain KY/07, or H7N9 Sh2 wild type containing Leu (L) at position 226 and mutants at this position harboring Ile (I) or Gln (Q). Shown are data representative of three independent experiments, each done in triplicate, with binding to α2-6 glycans in solid circles and α2-3 glycans in open squares. (B) The same recombinant HA proteins were used for assessment of receptor binding specificity on a glycan array. The mean signal and standard error were calculated from six independent replicates on the array. α2-3 sialosides are shown in white bars (glycans #3-35), α2-6 sialosides in black (glycans #36-56), and stripped bars denoted mixed bi-antennary glycans containing both α2-3 and α2-6 linked sialylated glycans (glycans #57, 58). Glycans imprinted on the array are listed in table S3.
Fig. 3
Fig. 3
Crystal structures of human Sh2 H7N9 HA in complex with receptor analogs. (A) Glycan structures of four receptor analogs commonly used for structural study. The purple diamond represents sialic acid (Sia), yellow circle represents galactose (Gal), blue squares represent N-acetyl glucosamine (GlcNAc), and blue circle represents glucose (Glc). (B) Avian receptor analog LSTa bound to human H7 HA. (C) Human receptor analog LSTc bound to human H7 HA. (D) Avian receptor analog 3′-SLN bound to avian H7 HA (PDB entry 4DJ7). (E) Human receptor analog LSTc bound to human H2 HA (PDB entry 2WR7).
Fig. 4
Fig. 4
Crystal structures of human Sh2 H7N9 HA in complex with three avian-type receptor glycans recognized in the glycan array. (A-C) Glycan compounds used for structural determination. The glycan portion that could be built in the final model is highlighted by a red dashed circle. The purple diamond represents sialic acid (Sia), yellow circle represents galactose (Gal), and blue and yellow squares represent N-acetyl glucosamine (GlcNAc) and N-acetyl galactosamine (GalNAc), respectively. (D) Sulfated glycan #3 bound to human H7N9 HA. (E) Glycan #21 bound to human H7N9 HA. (F) Biantennary glycan #23 bound to H7N9 HA using one of its two arms. (G) Superposition of glycan #23 (colored in purple), glycan #21 (in blue) and glycan #3 (in green) in the HA receptor binding site. Glycans #21 and #23 share a similar mode of ligand recognition.
Fig. 5
Fig. 5
Preferential binding of human Sh2 H7N9 HA to avian-type α2-3-linked glycans is achieved by flexible twisting of the glycan rings that create additional HA-glycan contacts away from Leu226. (A) Superposition of glycan #3 (cyan) and 3′-SLN (grey, from PDB entry 4DJ7) in the HA receptor binding site. (B) Superposition of glycan #21 (cyan) and 3′-SLN (grey) in the HA receptor binding site. (C) The sulfo group of glycan #3 is located near the amide nitrogen of Ser227 and within hydrogen bonding distance of Glu190. (D) Preferential binding to glycan #21 is mediated by hydrophilic interactions between Gln222 and the glycosidic linkage between GlcNAc-3 and GalNAc-4.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Emergence of avian influenza A(H7N9) virus causing severe human illness -China, February-April 2013. MMWR Morb Mortal Wkly Rep. 2013;62:366. - PMC - PubMed
    1. World Health Organization. Overview of the emergence and characteristics of the avian influenza A (H7N9) virus, 2013. http://www.who.int/influenza/human_animal_interface/influenza_h7n9/WHO_H....
    1. Gao R, et al. Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med. 2013;368:1888. - PubMed
    1. Li Q, et al. Preliminary report: epidemiology of the avian influenza A (H7N9) outbreak in China. N Engl J Med. 2013 Epub ahead of print.
    1. Morens DM, Taubenberger JK, Fauci AS. Pandemic influenza viruses--hoping for the road not taken. N Engl J Med. 2013;368:2345. - PMC - PubMed

Publication types

MeSH terms

-