The Interplay between the Host Receptor and Influenza Virus Hemagglutinin and Neuraminidase

Abstract

The hemagglutinin (HA) and neuraminidase (NA) glycoproteins of influenza A virus are responsible for the surface interactions of the virion with the host. Entry of the virus is mediated by functions of the HA: binding to cellular receptors and facilitating fusion of the virion membrane with the endosomal membrane. The HA structure contains receptor binding sites in the globular membrane distal head domains of the trimer, and the fusion machinery resides in the stem region. These sites have specific characteristics associated with subtype and host, and the differences often define species barriers. For example, avian viruses preferentially recognize α2,3-Sialic acid terminating glycans as receptors and mammalian viruses recognize α2,6-Sialic acid. The neuraminidase, or the receptor-destroying protein, cleaves the sialic acid from cellular membrane constituents and viral glycoproteins allowing for egress of nascent virions. A functional balance of activity has been demonstrated between the two glycoproteins, resulting in an optimum level of HA affinity and NA enzymatic cleavage to allow for productive infection. As more is understood about both HA and NA, the relevance for functional balance between HA and NA continues to expand, with potential implications for interspecies transmission, host adaptation, and pathogenicity.

Keywords: glycan binding; hemagglutinin; influenza A virus; neuraminidase; virus-host interactions.

Figure 1

The structure of N-acetylneuraminic acid, a type of sialic acid, in both linkage conformations.

Figure 2

(Left panel) Trimeric HA, with one monomer colored gray, another black, and the third monomer shown in blue (HA1) and red (HA2). The location of the receptor binding pocket for the monomer shown in blue and red is highlighted by the gray circle, and this region is magnified and reoriented in the right panel to depict structural features and conserved residues in the binding pocket, along with the location occupied by bound sialic acid, shown in green. All numbering based on H3 subtype.

Figure 3

Influenza A virus neuraminidase homotetramer. The catalytic site is shaded in gray on the colored monomer in the left panel. The right panels illustrate subtype differences in the catalytic sites by superimposing the subtypes shown (N4 and N8—top panel; and N2 and N9—lower panel) onto the N1 subtype (shown in green).

Figure 4

N-glycan core and complex structures. The core N-glycan is modified by the addition of subsequent monosaccharides to differentiate into oligomannose, complex or hybrid structures. Complex N-glycan structures relevant for IAV HA binding are shown.