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.
Highlights
The detection of microbial invasion by cells of the innate immune response occurs via receptor recognition of specific microbial molecular patterns, such as the Gram-negative lipopolysaccharide (LPS) endotoxin
We have identified a novel family of molecules secreted by medically-important helminth pathogens that exhibit striking structural, biochemical and functional similarities to host defence peptides, including LL-37
helminth defence molecules (HDMs) bind LPS preventing the activation of macrophages and the release of pro-inflammatory mediators that can cause sepsis
Summary
The detection of microbial invasion by cells of the innate immune response (macrophages and dendritic cells; DCs) occurs via receptor recognition of specific microbial molecular patterns (pathogen-associated molecular patterns; PAMPS), such as the Gram-negative lipopolysaccharide (LPS) endotoxin. Interaction between cell receptors and bacterial PAMPS drives the early immune response and leads to maturation of anti-microbial responses manifested in the production of potent pro-inflammatory cytokines such as IL-6, IL-12 and TNF [1]. While the production of these cytokines, together with up-regulation of costimulatory molecules on DCs, macrophages, granulocytes and mast cells, is a critical step in the development of appropriate protective adaptive immune responses, an excessive inflammatory response can lead to sepsis, septic shock and death [2,3]. Human defence peptides are potent signalling molecules released by cells of the innate immune system in response to cellular stimulation by microbes and pro-inflammatory mediators [4]. Defence peptides have been shown to suppress LPS-mediated responses [3,8], promote phagocytosis while inhibiting oxidant responses of neutrophils or monocytes [9,10], and inhibit proinflammatory cytokine secretion by macrophages in the presence of bacteria or other non-specific inflammatory stimuli [6,10]
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