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Review
. 2014 Mar 14;6(3):1294-316.
doi: 10.3390/v6031294.

Playing hide and seek: how glycosylation of the influenza virus hemagglutinin can modulate the immune response to infection

Michelle D Tate  1 , Emma R Job  2 , Yi-Mo Deng  3 , Vithiagaran Gunalan  4 , Sebastian Maurer-Stroh  5 , Patrick C Reading  6
Affiliations
Review

Playing hide and seek: how glycosylation of the influenza virus hemagglutinin can modulate the immune response to infection

Michelle D Tate et al. Viruses. .

Abstract

Seasonal influenza A viruses (IAV) originate from pandemic IAV and have undergone changes in antigenic structure, including addition of glycans to the hemagglutinin (HA) glycoprotein. The viral HA is the major target recognized by neutralizing antibodies and glycans have been proposed to shield antigenic sites on HA, thereby promoting virus survival in the face of widespread vaccination and/or infection. However, addition of glycans can also interfere with the receptor binding properties of HA and this must be compensated for by additional mutations, creating a fitness barrier to accumulation of glycosylation sites. In addition, glycans on HA are also recognized by phylogenetically ancient lectins of the innate immune system and the benefit provided by evasion of humoral immunity is balanced by attenuation of infection. Therefore, a fine balance must exist regarding the optimal pattern of HA glycosylation to offset competing pressures associated with recognition by innate defenses, evasion of humoral immunity and maintenance of virus fitness. In this review, we examine HA glycosylation patterns of IAV associated with pandemic and seasonal influenza and discuss recent advancements in our understanding of interactions between IAV glycans and components of innate and adaptive immunity.

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Figures

Figure 1
Figure 1
Structural models of the HA from different IAV subtypes showing glycosylation sites and attached glycans (yellow) on the head (blue) and stem (grey) of HA. HA proteins were derived from homology modeling based on representative strains from each subtype as indicated by * in Table 1. Glycosylation sites were derived from known glycosylated residues in closest known structures for each strain. Glycan molecules were manually added for each site using the Glyprot webserver [36] and energy minimisation was performed in Yasara (using the AMBER03 force field with default parameters) for glycans and adjacent HA atoms within 12Å as previously described [10]. Final models were rendered in POV-Ray [37]. Represenative HAs from H1N1, H2N2, H3N2, H5N1 and H7N9 viruses are shown.
Figure 2
Figure 2
Structural organisation of mammalian C-type lectins. (A) Soluble C-type lectins of the collectin family are comprised of subunits containing three polypeptide chains (shown as black lines), each containing a single C-terminal carbohydrate recognition domains (CRD) (shown in blue). Trimeric subunits associate together to form (i) multimers with a characteristic cruciform-like structure (e.g., surfactant protein (SP-D)), or (ii) higher-order multimers (e.g., SP-D), or (iii) multimers with a bouquet-like structure (e.g., mannose-binding lectin (MBL)). (B) Membrane-associated C-type lectins. The domain organization of the type II transmembrane proteins (i) macrophage galactose-type lectin (MGL) and (ii) DC-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) show a polypeptide chain containing a single CRD (shown in blue) which cluster together to form homo-oligomers on the cell surface. (iii) The macrophage mannose receptor (MMR) is a type I transmembrane protein which contains 8 CRDs (shown in blue) on a single polypeptide chain, as well as a cysteine-rich domain (red circle) and a fibronectin domain (purple square).
Figure 3
Figure 3
Schematic model showing recognition of glycan at Asn165 (Asn181) of H3 HA by SP-D or by Ab. An H3 trimer (blue) with glycosylation (yellow) at Asn165 (Asn181) is shown with one monomer in complex with an Ab (green) that is partially binding to glycan at Asn165 as seen in crystal structure PDB:1ken and another monomer in a modeled complex with a SP-D trimer (red, PDB:1pwb) binding the Asn165 glycan. Modeling and visualization were performed with Yasara [128].
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