Context-Specific Target Definition in Influenza A Virus Hemagglutinin-Glycan Receptor Interactions

Abstract

Summary Protein-glycan interactions are important regulators for a variety of biological processes, ranging from immune recognition to anticoagulation. An important area of active research is directed towards understanding the role of host cell surface glycans as recognition sites for pathogen protein receptors. Recognition of cell surface glycans is a widely employed strategy for a variety of pathogens, including bacteria, parasites, and viruses. We present here a representative example of such an interaction: the binding of influenza A hemagglutinin (HA) to specific sialylated glycans on the cell surface of human upper airway epithelial cells, which initiates the infection cycle. We detail a generalizable strategy to understand the nature of protein-glycan interactions both structurally and biochemically, using HA as a model system. This strategy combines a top-down approach using available structural information to define important contacts between glycans and HA, with a bottom-up approach using data mining and informatics approaches to identify the common motifs which distinguish glycan binders from non-binders. By probing protein-glycan interactions simultaneously through top-down and bottom-up approaches we can scientifically validate a series of observations. This in turn provides additional confidence and surmounts known challenges in the study of protein-glycan interactions, such as accounting for multivalency, and thus truly defines concepts such as specificity, affinity, and avidity. With the advent of new technologies for glycomics—including glycan arrays, data mining solutions, and robust algorithms to model protein-glycan interactions—we anticipate that such combination approaches will become tractable for a wide variety of protein-glycan interactions.

Glycan receptor specificity as a useful tool for characterization and surveillance of influenza A virus

“…A variety of biochemical methods have been used to characterize the specificity in the context of multivalent HA–glycan interactions (see review by Shriver et al [45] for an overview of these methods). Among the various tools, glycan array platforms are rapidly emerging as a popular tool to probe finer nuances of glycan structures that are recognized by various HAs [25–27].…”

Rethinking Approaches to Improve the Utilization of Nucleic Acid Amplification Tests for Detection and Characterization of Influenza A in Diagnostic and Reference Laboratories

“…These systems most likely would include glycan arrays, and re-engineered protein detection systems. Glycan arrays have been identified as an important tool in understanding how SNP changes and recombinations in the viral HA gene impact on the ability of the virus to bind to host cell glycans [151,152]. Biomarker detection may also be an approach that could be used for future diagnostics of IFVA.…”

Viral factors in influenza pandemic risk assessment

“…The involvement of other features in human adaptation, such as the topology of the bound HA-receptor complex, further complicate the genetic prediction of human adaptation, as the residues involved in these features are less well characterized (Shriver et al, 2009). …”