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, MW
dc.contributor.author Donnelly, S
dc.contributor.author Hutchinson, AT
dc.contributor.author To, J
dc.contributor.author Taylor, NL
dc.contributor.author Norton, RS
dc.contributor.author Perugini, MA
dc.contributor.author Dalton, JP
dc.date.accessioned 2012-10-12T03:34:25Z
dc.date.issued 2011-05
dc.identifier.citation PLoS Pathogens, 2011, 7 (5)
dc.identifier.issn 1553-7366
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 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. © 2011 Robinson et al.
dc.language eng
dc.relation.isbasedon 10.1371/journal.ppat.1002042
dc.title A family of helminth molecules that modulate innate cell responses via molecular mimicry of host antimicrobial peptides
dc.type Journal Article
dc.parent PLoS Pathogens
dc.journal.volume 5
dc.journal.volume 7
dc.journal.number 5 en_US
dc.publocation San Francisco en_US
dc.publocation Melbourne, Australia
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.conference Australasian Computing Education Conference
dc.for 0605 Microbiology
dc.personcode 995261
dc.personcode 030896
dc.personcode 100777
dc.personcode 100527
dc.personcode 030199
dc.percentage 100 en_US
dc.classification.name Microbiology en_US
dc.classification.type FOR-08 en_US
dc.edition en_US
dc.custom en_US
dc.date.activity en_US
dc.date.activity 2012-01-30
dc.location.activity en_US
dc.location.activity Melbourne, Australia
pubs.embargo.period Not known
pubs.organisational-group /University of Technology Sydney
pubs.organisational-group /University of Technology Sydney/Faculty of Science
pubs.organisational-group /University of Technology Sydney/Strength - Health Technologies
pubs.organisational-group /University of Technology Sydney/Strength - i3
utslib.copyright.status Open Access
utslib.copyright.date 2015-04-15 12:23:47.074767+10
pubs.consider-herdc true
utslib.collection.history School of Medical and Molecular Sciences (ID: 341)
utslib.collection.history School of Medical and Molecular Sciences (ID: 341)
utslib.collection.history General (ID: 2)


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