Cathelicidin-like Helminth Defence Molecules (HDMs): Absence of Cytotoxic, Anti-microbial and Anti-protozoan Activities Imply a Specific Adaptation to Immune Modulation

Abstract

Host defence peptides (HDPs) are expressed throughout the animal and plant kingdoms. They have multifunctional roles in the defence against infectious agents of mammals, possessing both bactericidal and immune-modulatory activities. We have identified a novel family of molecules secreted by helminth parasites (helminth defence molecules; HDMs) that exhibit similar structural and biochemical characteristics to the HDPs. Here, we have analyzed the functional activities of four HDMs derived from Schistosoma mansoni and Fasciola hepatica and compared them to human, mouse, bovine and sheep HDPs. Unlike the mammalian HDPs the helminth-derived HDMs show no antimicrobial activity and are non-cytotoxic to mammalian cells (macrophages and red blood cells). However, both the mammalian- and helminth-derived peptides suppress the activation of macrophages by microbial stimuli and alter the response of B cells to cytokine stimulation. Therefore, we hypothesise that HDMs represent a novel family of HDPs that evolved to regulate the immune responses of their mammalian hosts by retaining potent immune modulatory properties without causing deleterious cytotoxic effects.

A parasitic helminth-derived peptide that targets the macrophage lysosome is a novel therapeutic option for autoimmune disease

“…For example, the mammalian, but not the helminth, peptides displayed potent bactericidal activity (Thivierge et al, 2013). In addition, mammalian peptides were cytotoxic to macrophages at concentrations above 10 M, whereas the helminth peptides had no detectable deleterious effects on the cells, even at concentrations of 50 M (Thivierge et al, 2013). Accordingly, we proposed that despite having a similar structure, the distribution of positive charge across the peptides might distinguish the helminth and mammalian peptides, and confer different biological activities to each.…”

“…On the other hand, comparative studies of the mammalian HDPs and parasite HDMs revealed clear differences in their in vitro biological activities. For example, the mammalian, but not the helminth, peptides displayed potent bactericidal activity (Thivierge et al, 2013). In addition, mammalian peptides were cytotoxic to macrophages at concentrations above 10 M, whereas the helminth peptides had no detectable deleterious effects on the cells, even at concentrations of 50 M (Thivierge et al, 2013).…”

“…Favourably, the helminth parasite peptides are not cytotoxic to mammalian cells, even at high molecular concentrations (Thivierge et al, 2013). In addition, delivery of FhHDM-1 to mice does not induce the production of anti-FhHDM-1 antibodies, which would potentially neutralise its biological effect.…”

Fasciola hepatica Fatty Acid Binding Protein Induces the Alternative Activation of Human Macrophages

“…CatL1 and GST have been shown to activate dendritic cells via interaction with the pattern recognition receptor (PRR) Toll-like receptor 4 (TLR4) (15). F. hepatica and other helminth-derived peptides have also shown to suppress the activation of macrophages by microbial stimuli and to alter the response of B cells to cytokine stimulation (17,18). Total ESPs and recombinant versions of thioredoxin peroxidase have been shown to induce the alternative activation of macrophages in murine (14,19) and ruminant (16,20) models of fascioliasis.…”

A Trematode Parasite Derived Growth Factor Binds and Exerts Influences on Host Immune Functions via Host Cytokine Receptor Complexes

“…Cathepsin L1 has also been shown to cleave CD4 from the surface of lymphocytes [9] and prevent antibody-dependent cell cytotoxicity (ADCC) from killing newly excysted juvenile (NEJ) parasites [10]; one of the few mechanisms known to kill NEJs. More recently Donnelly and colleagues have shown multiple modes of immunosuppression involving a family of helminth defence molecules, similar to host defence peptides that are capable of suppressing macrophage activation and B-cell cytokine responses [11]; providing evidence parasite for mimicry.…”