Mini Review: Structure and Function of Nematode Phosphorylcholine-Containing Glycoconjugates

Abstract

An unusual aspect of the biology of nematodes is the covalent attachment of phosphorylcholine (PC) to carbohydrate in glycoconjugates. Investigation of the structure of these molecules by ever-increasingly sophisticated analytical procedures has revealed that PC is generally in phosphodiester linkage with C6 of N-acetylglucosamine (GlcNAc) in both N-type glycans and glycosphingolipids. Up to five PC groups have been detected in the former, being located on both antenna and core GlcNAc. The PC donor for transfer to carbohydrate appears to be phosphatidylcholine but the enzyme responsible for transfer remains to be identified. Work primarily involving the PC-containing Acanthocheilonema viteae secreted product ES-62, has shown that the PC attached to nematode N-glycans possesses a range of immunomodulatory properties, subverting for example, pro-inflammatory signalling in various immune system cell-types including lymphocytes, mast cells, dendritic cells and macrophages. This has led to the generation of PC-based ES-62 small molecule analogues (SMAs), which mirror the parent molecule in preventing the initiation or progression of disease in mouse models of a number of human conditions associated with aberrant inflammatory responses. These include rheumatoid arthritis, systemic lupus erythematosus and lung and skin allergy such that the SMAs are considered to have widespread therapeutic potential.

Unraveling cross-reactivity of anti-glycan IgG responses in filarial nematode infections

“…Given that several glycan features found in B. malayi are shared with other filarial nematodes, e.g. presence of PC ( 42 ) or terminal α-linked galactose (α-Gal) in GSLs ( 43 ), we evaluated the potential IgG cross-reactivity in plasma derived from other filarial nematode infections – L. loa , M. perstans , O. volvulus and W. bancrofti (n = 6 for each infection) – to B. malayi N-linked and GSL-derived glycans printed on the array. Results were compared to those obtained for B. malayi -infected individuals (n = 10), Ghanaian individuals not infected with filarial nematodes (n = 6) and uninfected European donors (n = 5).…”

“…A well-known shared feature of filarial nematodes is the presence of PC substituents, most of the time present in a phosphodiester linkage with C6 of the GlcNAc residues of N-linked and GSL glycans ( 42 ). Immunomodulatory properties of PC-containing epitopes have been extensively studied over the years ( 49 , 50 ), particularly in relation to the ES-62 glycoprotein of Acanthocheilonema viteae ( 51 , 52 ).…”

Epigenetic changes induced by parasitic worms and their excretory-secretory products

“…ES-62 is the major E–S product of the rodent filarial nematode Acanthocheilonema viteae [ 23 ]. The molecule is a tetrameric protein that contains multiple phosphorylcholine moieties attached to N -type glycans [ 24 ], which provide it with a range of immunomodulatory properties ( Figure 1 and reviewed in [ 25 ]). For example, in vitro exposure of antigen presenting cells such as BM-derived macrophages [ 26 ] or DCs [ 27 ] to ES-62 interferes with their ability to secrete cytokines IL-12 (can be pro-inflammatory, driving autoimmune conditions) in response to LPS.…”

“…The therapeutic potential of ES-62 has been alluded to earlier but as a large, foreign and hence potentially immunogenic protein and whose active moiety is dependent on a post translational event restricted to nematodes and perhaps a few other classes of lower organism, in reality ES-62 is unsuitable for use as a drug. For this reason, a library of PC-based ES-62 Small Molecule Analogues (SMAs) was developed [ 37 , 40 ] and found to contain members which mimicked the therapeutic potential of the parent molecule (reviewed in [ 25 , 34 ]). The ability to epigenetically rewire SFs demonstrated by ES-62 in the CIA model is also shared with these ES-62 SMAs as shown using SMA 12b as an example [ 36 ].…”

A novel family of sugar-specific phosphodiesterases that remove zwitterionic modifications ofN-acetylglucosamine

“…In eukaryotes, PC and PE have been observed on N-glycans from several invertebrates (3) and Penicillium fungi (4). They are prevalent on N-glycans and glycolipids of nematodes, including several mammalian parasite species (5)(6)(7)(8)(9)(10), where they help the parasite evade host immunity through inhibition of immune cell activity (6). Additionally, the eukaryotic glycosylphosphatidylinositol (GPI) anchor possesses a PE moiety that participates in linking the GPI to protein, and further side-branching PE residues decorate its glycan core in mammals and yeasts (11)(12)(13)(14).…”