A family of helminth molecules that modulate innate cell responses via molecular mimicry of host antimicrobial peptides.
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...
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2011
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oai:doaj.org-article:b058d9f038fc40e09234c67174aa24b42021-11-18T06:03:24ZA family of helminth molecules that modulate innate cell responses via molecular mimicry of host antimicrobial peptides.1553-73661553-737410.1371/journal.ppat.1002042https://doaj.org/article/b058d9f038fc40e09234c67174aa24b42011-05-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21589904/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Over 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.Mark W RobinsonSheila DonnellyAndrew T HutchinsonJoyce ToNicole L TaylorRaymond S NortonMatthew A PeruginiJohn P DaltonPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 7, Iss 5, p e1002042 (2011) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Mark W Robinson Sheila Donnelly Andrew T Hutchinson Joyce To Nicole L Taylor Raymond S Norton Matthew A Perugini John P Dalton A family of helminth molecules that modulate innate cell responses via molecular mimicry of host antimicrobial peptides. |
| description |
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. |
| format |
article |
| author |
Mark W Robinson Sheila Donnelly Andrew T Hutchinson Joyce To Nicole L Taylor Raymond S Norton Matthew A Perugini John P Dalton |
| author_facet |
Mark W Robinson Sheila Donnelly Andrew T Hutchinson Joyce To Nicole L Taylor Raymond S Norton Matthew A Perugini John P Dalton |
| author_sort |
Mark W Robinson |
| title |
A family of helminth molecules that modulate innate cell responses via molecular mimicry of host antimicrobial peptides. |
| title_short |
A family of helminth molecules that modulate innate cell responses via molecular mimicry of host antimicrobial peptides. |
| title_full |
A family of helminth molecules that modulate innate cell responses via molecular mimicry of host antimicrobial peptides. |
| title_fullStr |
A family of helminth molecules that modulate innate cell responses via molecular mimicry of host antimicrobial peptides. |
| title_full_unstemmed |
A family of helminth molecules that modulate innate cell responses via molecular mimicry of host antimicrobial peptides. |
| title_sort |
family of helminth molecules that modulate innate cell responses via molecular mimicry of host antimicrobial peptides. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2011 |
| url |
https://doaj.org/article/b058d9f038fc40e09234c67174aa24b4 |
| work_keys_str_mv |
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