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Novel Scabies Mite Serpins Inhibit the Three Pathways of the Human Complement System

In English

Författare

  • Angela Mika
  • Simone L. Reynolds
  • Frida Mohlin
  • Charlene Willis
  • Pearl M. Swe
  • Darren A. Pickering
  • Vanja Halilovic
  • Lakshmi C. Wijeyewickrema
  • Robert N. Pike
  • Anna Blom
  • David J. Kemp
  • Katja Fischer
Visa allt

Summary, in English

Scabies is a parasitic infestation of the skin by the mite Sarcoptes scabiei that causes significant morbidity worldwide, in particular within socially disadvantaged populations. In order to identify mechanisms that enable the scabies mite to evade human immune defenses, we have studied molecules associated with proteolytic systems in the mite, including two novel scabies mite serine protease inhibitors (SMSs) of the serpin superfamily. Immunohistochemical studies revealed that within mite-infected human skin SMSB4 (54 kDa) and SMSB3 (47 kDa) were both localized in the mite gut and feces. Recombinant purified SMSB3 and SMSB4 did not inhibit mite serine and cysteine proteases, but did inhibit mammalian serine proteases, such as chymotrypsin, albeit inefficiently. Detailed functional analysis revealed that both serpins interfered with all three pathways of the human complement system at different stages of their activation. SMSB4 inhibited mostly the initial and progressing steps of the cascades, while SMSB3 showed the strongest effects at the C9 level in the terminal pathway. Additive effects of both serpins were shown at the C9 level in the lectin pathway. Both SMSs were able to interfere with complement factors without protease function. A range of binding assays showed direct binding between SMSB4 and seven complement proteins (C1, properdin, MBL, C4, C3, C6 and C8), while significant binding of SMSB3 occurred exclusively to complement factors without protease function (C4, C3, C8). Direct binding was observed between SMSB4 and the complement proteases C1s and C1r. However no complex formation was observed between either mite serpin and the complement serine proteases C1r, C1s, MASP-1, MASP-2 and MASP-3. No catalytic inhibition by either serpin was observed for any of these enzymes. In summary, the SMSs were acting at several levels mediating overall inhibition of the complement system and thus we propose that they may protect scabies mites from complement-mediated gut damage.

Publiceringsår

2012

Språk

Engelska

Publikation/Tidskrift/Serie

PLoS ONE

Volym

7

Issue

7

Dokumenttyp

Artikel i tidskrift

Förlag

Public Library of Science (PLoS)

Ämne

  • Other Basic Medicine

Status

Published

Forskningsgrupp

  • Protein Chemistry, Malmö

ISBN/ISSN/Övrigt

  • ISSN: 1932-6203