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  • Review Article
  • Published:

Enabling the 'host jump': structural determinants of receptor-binding specificity in influenza A viruses

Nature Reviews Microbiology volume 12, pages 822–831 (2014)Cite this article

Subjects

Key Points

  • Interspecies transmission of influenza A viruses is the result of many factors. One of the key factors involved is a shift in the receptor-binding specificity of the virus, which is mostly determined by mutations in viral haemagglutinin (HA).

  • Recent structural studies have provided molecular insights into the HA–host receptor interactions that have enabled several influenza A virus subtypes to jump from avian to human hosts.

  • The combination of distinct amino acids at positions 225 and 190 of HA is important for determining the receptor-binding specificity of the H1 subtype.

  • The Q226L and G228S substitutions in the HA glycoproteins of the H2 and H3 subtypes are sufficient to change the binding preference from the avian receptor to the human receptor.

  • In an experimentally adapted H5 subtype, the Q226L substitution and loss of a glycosylation site near the receptor-binding site contribute to the shift in binding preference from the avian receptor to the human receptor.

  • In the H7 subtype, amino acid substitutions at positions 186 and 226 of HA increase the preference for binding to the human receptor.

Abstract

The recent emergence of the H7N9 avian influenza A virus and its ability to infect humans emphasize the epidemic and pandemic potential of these viruses. Interspecies transmission is the result of many factors, which ultimately lead to a change in the host tropism of the virus. One of the key factors involved is a shift in the receptor-binding specificity of the virus, which is mostly determined by mutations in the viral haemagglutinin (HA). In this Review, we discuss recent crystallographic studies that provide molecular insights into HA–host receptor interactions that have enabled several influenza A virus subtypes to 'jump' from avian to human hosts.

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Figure 1: Structure and life cycle of influenza A viruses.
Figure 2: The haemagglutinin binding site and host receptors.
Figure 3: Haemagglutinin proteins from the H1, H2 and H3 subtypes in complex with the avian and human receptor analogues.
Figure 4: Haemagglutinin proteins from the H5 and H7 subtypes in complex with the avian and human receptor analogues.

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Acknowledgements

Work in the authors' laboratory was supported by the China Ministry of Science and Technology National 973 Project (grant no. 2011CB504703), the National Natural Science Foundation of China (NSFC; grant no. 81290342 and 31402196) and intramural special grant for influenza virus research from the Chinese Academy of Sciences (KJZD-EW-L09). G.F.G. is a leading principal investigator of the NSFC Innovative Research Group (grant no. 81321063). Y.S. is supported by the Excellent Young Scientist Program of the Chinese Academy of Sciences. The authors are grateful to B. Tefsen and J. Haywood for their help in preparing the manuscript.

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Authors and Affiliations

  1. Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences (CAS), Beijing, 100101, China

    Yi Shi & George F. Gao

  2. CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China

    Yi Shi, Ying Wu, Wei Zhang, Jianxun Qi & George F. Gao

  3. Office of Director-General, Chinese Center for Disease Control and Prevention (China CDC), Beijing, 102206, China

    George F. Gao

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Herd immunity

(Also known as herd effect or community immunity). A form of immunity that occurs when the vaccination of a substantial portion of a population (or herd) provides a measure of protection for individuals who have not developed immunity.

Macropinocytic endocytosis

A process by which cells internalize molecules using a non-selective uptake pattern.

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A process by which cells internalize molecules in a receptor-mediated uptake pattern; it is also called receptor-mediated endocytosis.

Trans conformation

The conformation of a glycosidic linkage of receptor analogues, in which the two carbon atoms at either end of the glycosidic bond are oriented in opposing directions.

Cis conformation

The conformation of a glycosidic linkage of a receptor analogue, in which the two carbon atoms at either end of the glycosidic bond are oriented in the same direction.

Surface plasmon resonance

A method used to measure the interaction of macromolecules at a surface via changes in the refractive index.

Microarray

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Reassortant

A term that usually refers to a virus that contains two or more segments of nucleic acid (segmented genome) that are derived from different viruses.

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Shi, Y., Wu, Y., Zhang, W. et al. Enabling the 'host jump': structural determinants of receptor-binding specificity in influenza A viruses. Nat Rev Microbiol 12, 822–831 (2014). https://doi.org/10.1038/nrmicro3362

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