Fasciola hepatica serine protease inhibitor family (serpins): Purposely crafted for regulating host proteases.
Serine protease inhibitors (serpins) regulate proteolytic events within diverse biological processes, including digestion, coagulation, inflammation and immune responses. The presence of serpins in Fasciola hepatica excretory-secretory products indicates that the parasite exploits these to regulate...
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ftdoajarticles:oai:doaj.org/article:889313ea57b844b6a4f283fbc357103b 2023-05-15T15:13:24+02:00 Fasciola hepatica serine protease inhibitor family (serpins): Purposely crafted for regulating host proteases. Carolina De Marco Verissimo Heather L Jewhurst Irina G Tikhonova Rolf T Urbanus Aaron G Maule John P Dalton Krystyna Cwiklinski 2020-08-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0008510 https://doaj.org/article/889313ea57b844b6a4f283fbc357103b EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0008510 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0008510 https://doaj.org/article/889313ea57b844b6a4f283fbc357103b PLoS Neglected Tropical Diseases, Vol 14, Iss 8, p e0008510 (2020) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2020 ftdoajarticles https://doi.org/10.1371/journal.pntd.0008510 2022-12-31T07:16:57Z Serine protease inhibitors (serpins) regulate proteolytic events within diverse biological processes, including digestion, coagulation, inflammation and immune responses. The presence of serpins in Fasciola hepatica excretory-secretory products indicates that the parasite exploits these to regulate proteases encountered during its development within vertebrate hosts. Interrogation of the F. hepatica genome identified a multi-gene serpin family of seven members that has expanded by gene duplication and divergence to create an array of inhibitors with distinct specificities. We investigated the molecular properties and functions of two representatives, FhSrp1 and FhSrp2, highly expressed in the invasive newly excysted juvenile (NEJ). Consistent with marked differences in the reactive centre loop (RCL) that executes inhibitor-protease complexing, the two recombinant F. hepatica serpins displayed distinct inhibitory profiles against an array of mammalian serine proteases. In particular, rFhSrp1 efficiently inhibited kallikrein (Ki = 40 nM) whilst rFhSrp2 was a highly potent inhibitor of chymotrypsin (Ki = 0.07 nM). FhSrp1 and FhSrp2 are both expressed on the NEJ surface, predominantly around the oral and ventral suckers, suggesting that these inhibitors protect the parasites from the harmful proteolytic effects of host proteases, such as chymotrypsin, during invasion. Furthermore, the unusual inhibition of kallikrein suggests that rFhSrp1 modulates host responses such as inflammation and vascular permeability by interfering with the kallikrein-kinin system. A vaccine combination of rFhSrp1 and rFhSrp2 formulated in the adjuvant Montanide ISA 206VG elicited modest but non-significant protection against a challenge infection in a rat model, but did induce some protection against liver pathogenesis when compared to a control group and a group vaccinated with two well-studied vaccine candidates, F. hepatica cathepsin L2 and L3. This work highlights the importance of F. hepatica serpins to regulate host responses that ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLOS Neglected Tropical Diseases 14 8 e0008510 |
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Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
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ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Carolina De Marco Verissimo Heather L Jewhurst Irina G Tikhonova Rolf T Urbanus Aaron G Maule John P Dalton Krystyna Cwiklinski Fasciola hepatica serine protease inhibitor family (serpins): Purposely crafted for regulating host proteases. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Serine protease inhibitors (serpins) regulate proteolytic events within diverse biological processes, including digestion, coagulation, inflammation and immune responses. The presence of serpins in Fasciola hepatica excretory-secretory products indicates that the parasite exploits these to regulate proteases encountered during its development within vertebrate hosts. Interrogation of the F. hepatica genome identified a multi-gene serpin family of seven members that has expanded by gene duplication and divergence to create an array of inhibitors with distinct specificities. We investigated the molecular properties and functions of two representatives, FhSrp1 and FhSrp2, highly expressed in the invasive newly excysted juvenile (NEJ). Consistent with marked differences in the reactive centre loop (RCL) that executes inhibitor-protease complexing, the two recombinant F. hepatica serpins displayed distinct inhibitory profiles against an array of mammalian serine proteases. In particular, rFhSrp1 efficiently inhibited kallikrein (Ki = 40 nM) whilst rFhSrp2 was a highly potent inhibitor of chymotrypsin (Ki = 0.07 nM). FhSrp1 and FhSrp2 are both expressed on the NEJ surface, predominantly around the oral and ventral suckers, suggesting that these inhibitors protect the parasites from the harmful proteolytic effects of host proteases, such as chymotrypsin, during invasion. Furthermore, the unusual inhibition of kallikrein suggests that rFhSrp1 modulates host responses such as inflammation and vascular permeability by interfering with the kallikrein-kinin system. A vaccine combination of rFhSrp1 and rFhSrp2 formulated in the adjuvant Montanide ISA 206VG elicited modest but non-significant protection against a challenge infection in a rat model, but did induce some protection against liver pathogenesis when compared to a control group and a group vaccinated with two well-studied vaccine candidates, F. hepatica cathepsin L2 and L3. This work highlights the importance of F. hepatica serpins to regulate host responses that ... |
format |
Article in Journal/Newspaper |
author |
Carolina De Marco Verissimo Heather L Jewhurst Irina G Tikhonova Rolf T Urbanus Aaron G Maule John P Dalton Krystyna Cwiklinski |
author_facet |
Carolina De Marco Verissimo Heather L Jewhurst Irina G Tikhonova Rolf T Urbanus Aaron G Maule John P Dalton Krystyna Cwiklinski |
author_sort |
Carolina De Marco Verissimo |
title |
Fasciola hepatica serine protease inhibitor family (serpins): Purposely crafted for regulating host proteases. |
title_short |
Fasciola hepatica serine protease inhibitor family (serpins): Purposely crafted for regulating host proteases. |
title_full |
Fasciola hepatica serine protease inhibitor family (serpins): Purposely crafted for regulating host proteases. |
title_fullStr |
Fasciola hepatica serine protease inhibitor family (serpins): Purposely crafted for regulating host proteases. |
title_full_unstemmed |
Fasciola hepatica serine protease inhibitor family (serpins): Purposely crafted for regulating host proteases. |
title_sort |
fasciola hepatica serine protease inhibitor family (serpins): purposely crafted for regulating host proteases. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2020 |
url |
https://doi.org/10.1371/journal.pntd.0008510 https://doaj.org/article/889313ea57b844b6a4f283fbc357103b |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 14, Iss 8, p e0008510 (2020) |
op_relation |
https://doi.org/10.1371/journal.pntd.0008510 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0008510 https://doaj.org/article/889313ea57b844b6a4f283fbc357103b |
op_doi |
https://doi.org/10.1371/journal.pntd.0008510 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
14 |
container_issue |
8 |
container_start_page |
e0008510 |
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1766343956134625280 |