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

Karine Thivierge,Sheila M Donnelly,Deborah A Schaefer,Michael W Riggs,Sophie Cotton,John P Dalton,Joyce To,Mark W Robinson,Maria E Lund,Edward Mitre

doi:10.1371/journal.pntd.0002307

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.

Highlights

Host defence peptides (HDPs) are found in all living organisms and play a pivotal role as effector components of the innate immune system [1,2]
We identified a novel family of molecules secreted by medically-important helminth pathogens that exhibit striking structural and biochemical similarities to the HDPs
The parasite Helminth Defence Molecules (HDMs) displayed immune modulatory properties that were similar to their HDP homologs in mammals, but possessed no antimicrobial or cytotoxic activity

Summary

Introduction

Host defence peptides (HDPs) are found in all living organisms and play a pivotal role as effector components of the innate immune system [1,2]. They act as the first line of defence against pathogenic assaults from bacteria, fungi, eukaryotic parasites and viruses [3,4,5]. Despite the diversity in their sequences and structures, HDPs are typically small amphipathic peptides (12–50 amino acids) with a net positive charge (+2 to +9) and consist of at least 50% hydrophobic amino acids [10]. These biochemical properties are central to the HDPs antimicrobial function by allowing their interaction with, and disruption of, negatively charged bacterial membranes [10]

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Discussion

Conclusion