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.

Author Summary

In mammals, secreted host defence peptides (HDPs) protect against a wide range of infectious pathogens. They also perform a range of immune modulatory functions which regulate the immune response to pathogens, ensuring that the protective inflammatory response is not exacerbated and that post-infection repair mechanisms are initiated. We identified a novel family of molecules secreted by medically-important helminth pathogens (termed helminth defence molecules; HDMs) that exhibit striking structural and biochemical similarities to the HDPs. To further investigate the extent of this similarity, we have performed a comparative functional study between several well characterized, anti-microbial, mammalian HDPs and a series of parasite-derived peptides. The parasite HDMs displayed immune modulatory properties that were similar to their HDP homologs in mammals, but possessed no antimicrobial or cytotoxic activity. We propose that HDMs of these helminth pathogens underwent specific adaptation, losing their anti-microbial activity but retaining their ability to regulate the immune responses of their mammalian hosts. This absence of cytotoxicity and retention of immune-modulatory activity offers an opportunity to design novel immunotherapeutics derived from the HDMs which could be used to combat destructive inflammatory responses associated with microbial infection and immune-related disorders.