Glycans are or critical importance for many biological processes. They often contribute to physical and structural integrity, extracellular matrix formation, signal transduction, protein folding, information exchange between cells, and pathogen uptake. However, we know little about many of these functions because glycans are notoriously difficult to work with. My presentation will focus on the roles of glycans in viral attachment and bacterial cell wall structure. Many viruses use glycans that are linked to either a protein or a lipid as their primary or secondary receptor. Glycans terminating in sialic acid and its derivatives serve as particularly important receptors for a large number of viruses, including several human pathogens. Glycans are also key modifiers of bacterial cell wall molecules, with relevance for immune evasion.
In the first part of my presentation, I will present recent structure-function analyses of interactions of human pathogenic viruses with sialylated glycan-based cell attachment receptors. In combination with glycan array analyses, structural studies of complexes of viruses with sialylated oligosaccharides provide insights into the parameters that underlie each interaction. These analyses have helped to define common parameters of recognition, and they also serve as a platform for understanding the determinants of specificity. This information is highly useful for the prediction of the location of sialic acid binding sites in viruses for which structural information is still lacking. An improved understanding of the principles that govern the recognition of sialic acid and sialylated oligosaccharides can also advance efforts to develop efficient antiviral agents. Based on our structural data, we have begun to design ligands that can engage viral capsid proteins in adenoviruses and polyomaviruses with in some cases high affinity and increased specificity.
In the second part of my presentation, I will discuss the role of cell wall glycosylation of pathogenic bacteria for immune recognition. We have found that some multidrug-resistant strains of Staphylococcus aureus encode an enzyme called TarP that catalyzes the addition of GlcNAc to D-ribitol phosphate at a particular carbon atom (known as C3) in the ribitol chain of the wall teichoic acid. Normally, GlcNAc is added at a different position, the C4 carbon, by the action of a related enzyme called TarS. Surprisingly, the TarP enzyme is of viral origin and the result of the infection by a bacteriophage. TarP is dominant over its bacterial counterpart TarS. S. aureus is normally held in check because the immune system has the ability to detect it. However, we have found that the form of WTA made by TarP action is less likely to trigger an immune response in mice than is the form of WTA generated by TarS. indicating that TarP is crucial for the capacity of S. aureus to evade host defenses. The high-resolution structural analysis of TarP explains the mechanism of altered glycosylation and forms a template for targeted inhibition of TarP. We expect that our results will help with the identification of invariant S. aureus vaccine antigens and may enable the development of TarP inhibitors as a new strategy for rendering MRSA susceptible to human host defenses.