Glycan recognition at the saliva - oral microbiome interface

Abstract

The mouth is a first critical interface where most potentially harmful substances or pathogens contact the host environment. Adaptive and innate immune defense mechanisms are established there to inactivate or eliminate pathogenic microbes that traverse the oral environment on the way to their target organs and tissues. Protein and glycoprotein components of saliva play a particularly important role in modulating the oral microbiota and helping with the clearance of pathogens. It has long been acknowledged that glycobiological and glycoimmunological aspects play a pivotal role in oral host-microbe, microbe-host, and microbe-microbe interactions in the mouth. In this review, we aim to delineate how glycan-mediated host defense mechanisms in the oral cavity support human health. We will describe the role of glycans attached to large molecular size salivary glycoproteins which act as a first line of primordial host defense in the human mouth. We will further discuss how glycan recognition contributes to both colonization and clearance of oral microbes.

Keywords: Evolution; Glycans; Glycobiology; Host defense; Microbial adhesins; Microbiology; Mucins; Oral biology; Saliva; Salivary proteins.

Fig. 1.

Glycan-mediated interactions in the oral environment. A. Microbial attachment to the tooth surface. Microbial adhesins attach to mostly salivary glycoproteins adsorbed to the tooth surface as part of the acquired enamel pellicle. This is typically the first step in oral biofilm formation. B. Microbial adhesins attach to glycans on other microbes. This example shows microbial coadhesion, the process of attaching to microbes that are part of a biofilm. If this microbe-microbe attachment occurs in suspension, i.e. in the planktonic phase, it is called microbial coaggregation. C. Microbial adhesins attach to glycans on oral epithelia. This interaction normally does not result in long-term colonization because the oral epithelium is a shedding surface. D. Salivary glycoproteins agglutinate microbes. Natural salivary flow causes these aggregates to be swallowed, resulting in clearance of the microbes from the oral cavity. E. Salivary glycoproteins can serve as molecular camouflage. A microbial cells is covered by multiple bound salivary agglutinins and mucins. This might protect the microbe from immune surveillance by masking the underlying microbial cell surface. F. Lectin-mediated phagocytosis. Phagocyte lectins bind to microbial glycans, and microbial adhesins bind to phagocyte glycans. These interactions can both potentially lead to phagocyte activation and phagocytosis of the bacteria.

Fig. 2.

Typical salivary glycoproteins and their glycans. A. Mucins. Shown is a schematic diagram of the salivary mucin MUC7. The mucin protein backbone (apomucin) contains tandem repeats of proline, serine, and threonine-rich (PTS) domains, which are densely O-glycosylated. Non-repeat regions at the N- and C-terminals can be both O- and N-glycosylated. Dense O-glycosylation is believed to prevent typical protein folding, resulting in a bottle-brush-like shape. The larger gel-forming mucins such as MUC5B (not shown) are composed of several covalently linked mucin subunits. B. Agglutinins. Shown is a schematic diagram of the salivary agglutinin gp340/DMBT1. This protein contains several scavenger receptor cysteine-rich (SRCR) domains, which constitute the majority of the protein [263]. The SRCR domains often mediate ligand binding or protein-protein interactions with microbes. N-glycosylation occurs within the SRCR domains, and O-glycosylation occurs between the SRCR domains in serine-threonine-rich motifs that are approximately 20 amino acids in length [264]. C. Representation of a typical O-glycan chain. The base of an O-glycan is typically comprised of GalNAc α-linked to the hydroxyl group of serine or threonine. Other specific saccharide subunits and their attachments vary, but there are often two major branches with a small number of subunits. D. Representation of a typical Nglycan. N-glycans are attached to asparagine. All of the characterized eukaryotic N-glycans begin with a GlcNAcβ1-Asn linkage, but other saccharide linkages have been observed in prokaryotes. N-glycans are generally larger than O-glycans, containing more saccharide subunits and two to four major branches.