Scabies mite inactive serine proteases are potent inhibitors of the human complement lectin pathway.
Scabies is an infectious skin disease caused by the mite Sarcoptes scabiei and has been classified as one of the six most prevalent epidermal parasitic skin diseases infecting populations living in poverty by the World Health Organisation. The role of the complement system, a pivotal component of hu...
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ftdoajarticles:oai:doaj.org/article:706de1d5d44c43ed863bd5b2d19e78cb 2023-05-15T15:15:20+02:00 Scabies mite inactive serine proteases are potent inhibitors of the human complement lectin pathway. Simone L Reynolds Robert N Pike Angela Mika Anna M Blom Andreas Hofmann Lakshmi C Wijeyewickrema Dave Kemp Katja Fischer 2014-05-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0002872 https://doaj.org/article/706de1d5d44c43ed863bd5b2d19e78cb EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC4031079?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0002872 https://doaj.org/article/706de1d5d44c43ed863bd5b2d19e78cb PLoS Neglected Tropical Diseases, Vol 8, Iss 5, p e2872 (2014) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2014 ftdoajarticles https://doi.org/10.1371/journal.pntd.0002872 2022-12-31T06:04:08Z Scabies is an infectious skin disease caused by the mite Sarcoptes scabiei and has been classified as one of the six most prevalent epidermal parasitic skin diseases infecting populations living in poverty by the World Health Organisation. The role of the complement system, a pivotal component of human innate immunity, as an important defence against invading pathogens has been well documented and many parasites have an arsenal of anti-complement defences. We previously reported on a family of scabies mite proteolytically inactive serine protease paralogues (SMIPP-Ss) thought to be implicated in host defence evasion. We have since shown that two family members, SMIPP-S D1 and I1 have the ability to bind the human complement components C1q, mannose binding lectin (MBL) and properdin and are capable of inhibiting all three human complement pathways. This investigation focused on inhibition of the lectin pathway of complement activation as it is likely to be the primary pathway affecting scabies mites. Activation of the lectin pathway relies on the activation of MBL, and as SMIPP-S D1 and I1 have previously been shown to bind MBL, the nature of this interaction was examined using binding and mutagenesis studies. SMIPP-S D1 bound MBL in complex with MBL-associated serine proteases (MASPs) and released the MASP-2 enzyme from the complex. SMIPP-S I1 was also able to bind MBL in complex with MASPs, but MASP-1 and MASP-2 remained in the complex. Despite these differences in mechanism, both molecules inhibited activation of complement components downstream of MBL. Mutagenesis studies revealed that both SMIPP-Ss used an alternative site of the molecule from the residual active site region to inhibit the lectin pathway. We propose that SMIPP-Ss are potent lectin pathway inhibitors and that this mechanism represents an important tool in the immune evasion repertoire of the parasitic mite and a potential target for therapeutics. Article in Journal/Newspaper Arctic Mite Directory of Open Access Journals: DOAJ Articles Arctic PLoS Neglected Tropical Diseases 8 5 e2872 |
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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 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Simone L Reynolds Robert N Pike Angela Mika Anna M Blom Andreas Hofmann Lakshmi C Wijeyewickrema Dave Kemp Katja Fischer Scabies mite inactive serine proteases are potent inhibitors of the human complement lectin pathway. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
Scabies is an infectious skin disease caused by the mite Sarcoptes scabiei and has been classified as one of the six most prevalent epidermal parasitic skin diseases infecting populations living in poverty by the World Health Organisation. The role of the complement system, a pivotal component of human innate immunity, as an important defence against invading pathogens has been well documented and many parasites have an arsenal of anti-complement defences. We previously reported on a family of scabies mite proteolytically inactive serine protease paralogues (SMIPP-Ss) thought to be implicated in host defence evasion. We have since shown that two family members, SMIPP-S D1 and I1 have the ability to bind the human complement components C1q, mannose binding lectin (MBL) and properdin and are capable of inhibiting all three human complement pathways. This investigation focused on inhibition of the lectin pathway of complement activation as it is likely to be the primary pathway affecting scabies mites. Activation of the lectin pathway relies on the activation of MBL, and as SMIPP-S D1 and I1 have previously been shown to bind MBL, the nature of this interaction was examined using binding and mutagenesis studies. SMIPP-S D1 bound MBL in complex with MBL-associated serine proteases (MASPs) and released the MASP-2 enzyme from the complex. SMIPP-S I1 was also able to bind MBL in complex with MASPs, but MASP-1 and MASP-2 remained in the complex. Despite these differences in mechanism, both molecules inhibited activation of complement components downstream of MBL. Mutagenesis studies revealed that both SMIPP-Ss used an alternative site of the molecule from the residual active site region to inhibit the lectin pathway. We propose that SMIPP-Ss are potent lectin pathway inhibitors and that this mechanism represents an important tool in the immune evasion repertoire of the parasitic mite and a potential target for therapeutics. |
format |
Article in Journal/Newspaper |
author |
Simone L Reynolds Robert N Pike Angela Mika Anna M Blom Andreas Hofmann Lakshmi C Wijeyewickrema Dave Kemp Katja Fischer |
author_facet |
Simone L Reynolds Robert N Pike Angela Mika Anna M Blom Andreas Hofmann Lakshmi C Wijeyewickrema Dave Kemp Katja Fischer |
author_sort |
Simone L Reynolds |
title |
Scabies mite inactive serine proteases are potent inhibitors of the human complement lectin pathway. |
title_short |
Scabies mite inactive serine proteases are potent inhibitors of the human complement lectin pathway. |
title_full |
Scabies mite inactive serine proteases are potent inhibitors of the human complement lectin pathway. |
title_fullStr |
Scabies mite inactive serine proteases are potent inhibitors of the human complement lectin pathway. |
title_full_unstemmed |
Scabies mite inactive serine proteases are potent inhibitors of the human complement lectin pathway. |
title_sort |
scabies mite inactive serine proteases are potent inhibitors of the human complement lectin pathway. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2014 |
url |
https://doi.org/10.1371/journal.pntd.0002872 https://doaj.org/article/706de1d5d44c43ed863bd5b2d19e78cb |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic Mite |
genre_facet |
Arctic Mite |
op_source |
PLoS Neglected Tropical Diseases, Vol 8, Iss 5, p e2872 (2014) |
op_relation |
http://europepmc.org/articles/PMC4031079?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0002872 https://doaj.org/article/706de1d5d44c43ed863bd5b2d19e78cb |
op_doi |
https://doi.org/10.1371/journal.pntd.0002872 |
container_title |
PLoS Neglected Tropical Diseases |
container_volume |
8 |
container_issue |
5 |
container_start_page |
e2872 |
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1766345689538756608 |