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 ofN-acetylglucosamine (GlcNAc) in bothN-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-containingAcanthocheilonema viteaesecreted product ES-62, has shown that the PC attached to nematodeN-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.
Highlights
During the human-infectious stage of the helminthic life cycle, parasites engage in a series of actions designed to evade the host immune response [1]
Sophisticated analytical procedures are being applied to the elucidation of the structure of nematode PCcontaining glycoconjugates
PC-containing nematode glycoconjugates possess immunomodulatory properties such that they are potentially therapeutic but full exploitation of this with respect to PC-containing glycoproteins such as ES-62 is handicapped by an inability to produce fully active recombinant forms, as no convenient protein expression system exists that encodes the requisite PC transferase enzyme [109,110,111,112]
Summary
During the human-infectious stage of the helminthic life cycle, parasites engage in a series of actions designed to evade the host immune response [1]. Molecules closely mimicking the original ES-62 PC-glycan structures (Figure 1) have been detected in anthropophilic filarial species B. malayi, Onchocerca volvulus, Wucheria bancrofti and Loa loa, and in B. pahangi (feline), O. gibsoni (bovine) and Dirofilaria immitis (canine) species [12, 13, 17, 19] Outside of filaria, these PC-glycan structures remain relatively consistent in parasitic nematodes; Trichinella spiralis produces glycans which appear to bear PC moieties likely attached to GlcNAc residues on a trimmed trimannosyl core, this is followed by further GalNAc transferase activity to extend the antenna [24]. The PC-containing molecules inhibit B cell receptor (BCR)-stimulated phosphoinositide-3kinase (PI3K) and protein kinase C activities [35,36,37], as well as reducing the phosphorylation of Igb and the adaptor Shc resulting in reduced Erk1/2 MAPK activation [37, 38]. This functionality may benefit parasitic worms by sequestering components of the complement cascade, resulting in a low complement activation state
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