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

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dc.contributor.author Robinson, Mark en_US
dc.contributor.author Donnelly, Sheila en_US
dc.contributor.author Hutchinson, Andrew en_US
dc.contributor.author To, Joyce en_US
dc.contributor.author Taylor, Nicole en_US
dc.contributor.author Norton, Raymond en_US
dc.contributor.author Perugini, Matthew en_US
dc.contributor.author Dalton, John en_US
dc.contributor.editor en_US
dc.date.accessioned 2012-10-12T03:34:25Z
dc.date.available 2012-10-12T03:34:25Z
dc.date.issued 2011 en_US
dc.identifier 2011000515 en_US
dc.identifier.citation Robinson Mark et al. 2011, 'A Family of Helminth Molecules that Modulate Innate Cell Responses via Molecular Mimicry of Host Antimicrobial Peptides', Public Library Science, vol. 7, no. 5, pp. e1002042 en_US
dc.identifier.issn 1553-7366 en_US
dc.identifier.other C1 en_US
dc.identifier.uri http://hdl.handle.net/10453/18609
dc.description.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 alpha-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. en_US
dc.language en_US
dc.publisher Public Library Science en_US
dc.title A Family of Helminth Molecules that Modulate Innate Cell Responses via Molecular Mimicry of Host Antimicrobial Peptides en_US
dc.parent Plos Pathogens en_US
dc.journal.volume 7 en_US
dc.journal.number 5 en_US
dc.publocation San Francisco en_US
dc.identifier.startpage 1 en_US
dc.identifier.endpage en_US
dc.identifier.endpage 15 en_US
dc.cauo.name SCI.Faculty of Science en_US
dc.conference Verified OK en_US
dc.for 111601 en_US
dc.personcode 100777 en_US
dc.personcode 995261 en_US
dc.personcode 100527 en_US
dc.personcode 030199 en_US
dc.personcode 0000068437 en_US
dc.personcode 0000020341 en_US
dc.personcode 0000059270 en_US
dc.personcode 030896 en_US
dc.percentage 100 en_US
dc.classification.name Cell Physiology en_US
dc.classification.type FOR-08 en_US
dc.edition en_US
dc.custom en_US
dc.date.activity en_US
dc.location.activity en_US
dc.description.keywords Alternatively Activated Macrophages; Protein Secondary Structure; Pathogen Fasciola-Hepatica; Circular-Dichroism Spectra; Size-Distribution Analysis; Defense Peptides; Lipopolysaccharide-Binding; Cathelicidin Family; Enteric Nematode; Immune-Response en_US
dc.staffid 030896 en_US


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