Receptor Binding Properties of Neuraminidase for influenza A virus: An Overview of Recent Research Advances

Abstract

Influenza A viruses (IAVs) pose a serious risk to both human and animal health. IAVs' receptor binding characteristics account for a major portion of their host range and tissue tropism. While the function of neuraminidase (NA) in promoting the release of progeny virus is well-known, its role in the virus entry process remains poorly understood. Studies have suggested that certain subtypes of NA can act as receptor-binding proteins, either alone or in conjunction with haemagglutinin (HA). An important distinction is that NA from the avian influenza virus have a second sialic acid-binding site (2SBS) that is preserved in avian strains but missing in human or swine strains. Those observations suggest that the 2SBS may play a key role in the adaptation of the avian influenza virus to mammalian hosts. In this review, we provide an update of the recent research advances in the receptor-binding role of NA and highlight its underestimated importance during the early stages of the IAV life cycle. By doing so, we aim to provide new insights into the mechanisms underlying IAV host adaptation and pathogenesis.

Keywords: Neuraminidase; avian influenza virus; host adaptation; influenza a virus; interspecies transmission; second sialic acid-binding site.

Figure 1.

(a) the structure of the NA protein tetrad displaying the head region is depicted. Each monomer is shown to have an SA residue attached to its head, which serves as the site of enzyme activity. (b) the four polypeptide monomers of NA fold and assemble into a tetrameric structure encompassing a spherical head region, a stem, a transmembrane region, and a cytoplasmic tail. The head region of the depicted NA was derived from the Protein Data Bank (PDB:4GZW), and the corresponding protein model was generated using Pymol software. (c) the relative positions of the enzyme active site (highlighted in yellow) and the second receptor binding site (highlighted in blue and red: 366–373, 399–404, 430–433) at the head region of each NA monomer are shown, with the red area (364, 367, 369, 400, 403, 432) denoting the contact site of the second receptor binding site of NA. The location of the D151G mutation is illustrated in green. Each monomer binds to an α-2,3 sialic acid (SA). The NA structure displayed in the figure was obtained from the Protein Data Bank (PDB:4GZW), and the protein model was generated using Pymol software.

Figure 2.

The sequence of the three loops (residues 366 to 373), 400 loop (residues 399 to 404), and 430 loop (residues 430 to 433) that form the second receptor binding site of the N1, N2, and N9 in humans and birds. This Seqlogo was generated by the WebLogo program (http://weblogo.berkeley.edu/logo.cgi) using strains retrieved from the GenBank database.