Glycan-protein interactions in viral pathogenesis

Abstract

The surfaces of host cells and viruses are decorated by complex glycans, which play multifaceted roles in the dynamic interplay between the virus and the host including viral entry into host cell, modulation of proteolytic cleavage of viral proteins, recognition and neutralization of virus by host immune system. These roles are mediated by specific multivalent interactions of glycans with their cognate proteins (generally termed as glycan-binding proteins or GBPs or lectins). The advances in tools and technologies to chemically synthesize and structurally characterize glycans and glycan-GBP interactions have offered several insights into the role of glycan-GBP interactions in viral pathogenesis and have presented opportunities to target these interactions for novel antiviral therapeutic or vaccine strategies. This review covers aspects of role of host cell surface glycan receptors and viral surface glycans in viral pathogenesis and offers perspectives on how to employ various analytical tools to target glycan-GBP interactions.

Figure 1

Schematic of complex glycans in the interplay between virus and host. Shown in the figure (on the left) is a schematic of a virus surface glycoprotein (such as influenza A virus hemagglutinin) that recognized glycans on the host cell surface as their primary receptors for viral attachment and entry. The viral surface protein is in itself glycosylated and depending on the site of glycan occupancy, the glycosylation would impact the binding of this protein to the host-cell glycan receptor. Shown on the right is a schematic of glycan on the surface of virus envelop proteins (such as dengue) interacting with GBP anchored on the host cell. This interaction could either be beneficial for the virus wherein it plays a role in viral attachment and entry into a cell capable of promoting the productive infection or it could be beneficial to the host wherein antigen presenting cells could uptake the virus and prime the host immune response.

Figure 2

Tools to define glycan-specific targets in viral–host interactions. (a) Shows snapshots of various analytical tools that either directly probe glycans in the appropriate physiological context (such as lectin-based staining and lectin array) or provide detailed characterization of glycans isolated from host or viral surface (using mass spectrometry and NMR based approaches. (b) Shows analysis of GBPs and their glycan-binding site using a network approach which not only takes into account key residues in glycan-binding but also those that are related to these residues through their inter-residue interaction network. (c) Shows a schematic of biochemical (top) and structural (bottom) tools to probe glycan–GBP interactions. As shown in the bottom, shape based definitions of the conformational space sampled by glycans relates the conformations defined by 7 different glyosidic torsion angle (for a tetrasaccharide) into a single parameter θ whose variation can be studied during molecular dynamics simulations.