A Family of Helminth Molecules that Modulate Innate Cell Responses via Molecular Mimicry of Host Antimicrobial Peptides

Abstract

Over the last decade a significant number of studies have highlighted the central role of host antimicrobial (or defence) peptides in modulating the response of innate immune cells to pathogen-associated ligands. In humans, the most widely studied antimicrobial peptide is LL-37, a 37-residue peptide containing an amphipathic helix that is released via proteolytic cleavage of the precursor protein CAP18. Owing to its ability to protect against lethal endotoxaemia and clinically-relevant bacterial infections, LL-37 and its derivatives are seen as attractive candidates for anti-sepsis therapies. We have identified a novel family of molecules secreted by parasitic helminths (helminth defence molecules; HDMs) that exhibit similar biochemical and functional characteristics to human defence peptides, particularly CAP18. The HDM secreted by Fasciola hepatica (FhHDM-1) adopts a predominantly α-helical structure in solution. Processing of FhHDM-1 by F. hepatica cathepsin L1 releases a 34-residue C-terminal fragment containing a conserved amphipathic helix. This is analogous to the proteolytic processing of CAP18 to release LL-37, which modulates innate cell activation by classical toll-like receptor (TLR) ligands such as lipopolysaccharide (LPS). We show that full-length recombinant FhHDM-1 and a peptide analogue of the amphipathic C-terminus bind directly to LPS in a concentration-dependent manner, reducing its interaction with both LPS-binding protein (LBP) and the surface of macrophages. Furthermore, FhHDM-1 and the amphipathic C-terminal peptide protect mice against LPS-induced inflammation by significantly reducing the release of inflammatory mediators from macrophages. We propose that HDMs, by mimicking the function of host defence peptides, represent a novel family of innate cell modulators with therapeutic potential in anti-sepsis treatments and prevention of inflammation. The study of pharmacologically active peptides is central to the understanding of disease and the development of novel therapies. Of particular interest is the array of short cationic peptides, collectively known as antimicrobial (or host defence) peptides. In humans, the most widely studied host defence peptide is LL-37. This α-helical peptide is expressed by neutrophils, macrophages and mucosal epithelial cells and modulates the response of innate immune cells to pathogen-associated ligands (such as bacterial lipopolysaccharide). We have identified a novel family of molecules secreted by medically-important helminth pathogens (termed helminth defence molecules; HDMs) that exhibit striking structural, biochemical and functional similarities to host defence peptides, including LL-37. HDMs bind LPS preventing the activation of macrophages and the release of pro-inflammatory mediators that can cause sepsis. We propose that HDMs modulate the immune response via molecular mimicry of host defence peptides, thus creating a unique opportunity for novel anti-infective therapy.