Helminth Glycans at the Host-Parasite Interface and Their Potential for Developing Novel Therapeutics

Abstract

Helminths are parasitic worms that have successfully co-evolved with their host immune system to sustain long-term infections. Their successful parasitism is mainly facilitated by modulation of the host immune system via the release of excretory-secretory (ES) products covered with glycan motifs such as Lewis X, fucosylated LDN, phosphorylcholine and tyvelose. Evidence is accumulating that these glycans play key roles in different aspects of helminth infection including interactions with immune cells for recognition and evasion of host defences. Moreover, antigenic properties of glycans can be exploited for improving the efficacy of anti-helminthic vaccines. Here, we illustrate that glycans have the potential to open new avenues for the development of novel biopharmaceuticals and effective vaccines based on helminth glycoproteins.

Keywords: biopharmaceuticals; glycans; helminths; immunomodulation; vaccines.

FIGURE 1

Overview of a selection of helminth glycans with strong immunogenic or immunomodulatory properties. The corresponding positions and symbols of the monosaccharide units are indicated. LDN and (multi)-fucosylated LDN found on secreted egg antigens of the trematode Schistosoma mansoni are associated with immunogenic responses whereas Lewis X has immunomodulatory effects. In contrast to the other glycan motifs, multi-fucosylated LDN is found on O-glycans. Tyvelose expressed by Trichinella species and distal core fucose expressed by Haemonchus contortus are glycan motifs which are associated to be important to induce humoral immunity. Glycoproteins carrying phosphorylcholine (PC) are mainly secreted by filarial nematodes and in many cases, PC is responsible for the immunomodulatory effects of these glycoproteins.

FIGURE 2

Internal signalling of dendritic cells upon exposure of glycoproteins omega-1 and ES-62. C-type lectin receptors can bind various glycan motifs such as LeX on omega-1, which results in uptake of the extracellular antigen. After internalisation in endosomes (1), omega-1 translocates to the cytosol where it interferes with protein translation by exhibiting RNase activity on messenger RNA and ribosomal RNA (2). This suppresses DC maturation by inhibiting IL-12 cytokine release whilst enhancing IL-10 production and down-regulation of co-stimulatory molecules such as CD86. This ultimately results in T helper 2 (Th2) cell polarisation (3). Glycoprotein ES-62 biases the immune system towards an anti-inflammatory/Th2 response as it is able to mediate the LPS-induced TLR4 signalling by regulating the activity of kinases Erk, JNK and p38 via adaptor molecule MyD88 (4). This leads to down-regulation of gene transcription of Th1-associated cytokines (IL-6, IL-12p38 subunit and TNF-α) (5). ES-62 inhibits the production of IL-12p40 subunit by preventing the binding of transcription factor NF-κB to the IL-12 promotor (6).