Infection, inflammation and host carbohydrates: a Glyco-Evasion Hypothesis

Abstract

Microbial immune evasion can be achieved through the expression, or mimicry, of host-like carbohydrates on the microbial cell surface to hide from detection. However, disparate reports collectively suggest that evasion could also be accomplished through the modulation of the host glycosylation pathways, a mechanism that we call the "Glyco-Evasion Hypothesis". Here, we will summarize the evidence in support of this paradigm by reviewing three separate bodies of work present in the literature. We review how infection and inflammation can lead to host glycosylation changes, how host glycosylation changes can increase susceptibility to infection and inflammation and how glycosylation impacts molecular and cellular function. Then, using these data as a foundation, we propose a unifying hypothesis in which microbial products can hijack host glycosylation to manipulate the immune response to the advantage of the pathogen. This model reveals areas of research that we believe could significantly improve our fight against infectious disease.

Fig. 1.

Man2a1 is an enzyme in the N-glycosylation pathway that removes the terminal α1-3Man and α1-6Man residues from the GlcNAcMan₅GlcNAc₁ structure. Without the removal of these two mannose residues, branched complex-type N-glycans are not formed. However, the terminal β1-2-linked GlcNAc can be extended (arrow) by the cohort of Golgi enzymes present.

Fig. 2.

The bovine herpesvirus 4-encoded β1,6-GlcNAc transferase (Bo17/β1,6GnT) shown in red is a homolog of Gcnt1, the host transferase that adds GlcNAc to the “core 2” O-glycan (core 2 GlcNAcT). The microbial expression of this enzyme could lead to significant increases in core 2 structures, which are known to decrease the interactions of a number of cells, including immune cells (Fukuda and Tsuboi 1999).

Fig. 3.

GlcNAc transferases I, II, IV and V are necessary for the synthesis of mono-, bi-, tri- and tetra-antennary branched complex-type N-glycans, although mono-antennary structures are quite rare. This figure provides a framework of possible modifications; however, the glycans shown represent a very small fraction of the variety than can occur through differing the sugar linkages of those shown (e.g. α2,3- vs α2-6-linked sialic acids) and the action of a host of enzymes that include fucosyltransferases, galactosyltransferases, sulfotransferases and so on.

Fig. 4.

Sialyl-Lewis^x (SLe^x) antigen (boxed) is a tetrasaccharide motif composed of a sialic acid, galactose, GlcNAc and fucose residue. This motif can be found in both asparagine (N)-linked complex glycans, “core 2” and “core 4” serine or threonine (O)-linked glycans, as well as in glycolipids. Examples of both protein-based glycans are shown.