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


Autoria(s): Robinson, Mark W; Donnelly, Sheila; Hutchinson, Andrew T; To, Joyce; Taylor, Nicole L; Norton, Raymond S; Perugini, Matthew A; Dalton, John P
Data(s)

01/05/2011

Resumo

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.

Identificador

http://pure.qub.ac.uk/portal/en/publications/a-family-of-helminth-molecules-that-modulate-innate-cell-responses-via-molecular-mimicry-of-host-antimicrobial-peptides(08291456-fa01-4c2c-aebb-6a34d9689297).html

http://dx.doi.org/10.1371/journal.ppat.1002042

Idioma(s)

eng

Direitos

info:eu-repo/semantics/restrictedAccess

Fonte

Robinson , M W , Donnelly , S , Hutchinson , A T , To , J , Taylor , N L , Norton , R S , Perugini , M A & Dalton , J P 2011 , ' A Family of Helminth Molecules that Modulate Innate Cell Responses via Molecular Mimicry of Host Antimicrobial Peptides ' PLoS Pathogens , vol 7 , no. 5 , e1002042 , pp. e1002042 . DOI: 10.1371/journal.ppat.1002042

Palavras-Chave #/dk/atira/pure/subjectarea/asjc/1300/1311 #Genetics #/dk/atira/pure/subjectarea/asjc/1300/1312 #Molecular Biology #/dk/atira/pure/subjectarea/asjc/2400/2403 #Immunology #/dk/atira/pure/subjectarea/asjc/2400/2404 #Microbiology #/dk/atira/pure/subjectarea/asjc/2400/2405 #Parasitology #/dk/atira/pure/subjectarea/asjc/2400/2406 #Virology
Tipo

article