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* Department of Laboratory Medicine, Wallenberg Laboratory, University Hospital Malmö, Lund University, Malmö, Sweden;
Infectious Diseases and Immunology Division, Queensland Institute of Medical Research, Brisbane, Australia;
School of Veterinary Sciences, The University of Queensland, St. Lucia, Australia; and
Department of Biochemistry & Molecular Biology, Monash University, Clayton, Victoria, Australia
Infestation of skin by the parasitic itch mite Sarcoptes scabiei afflicts 300 million people worldwide and there is a need for novel and efficient therapies. We have previously identified a multigene family of serine proteases comprising multiple catalytically inactive members (scabies mite-inactivated protease paralogs (SMIPPs)), which are secreted into the gut of S. scabiei. SMIPPs are located in the mite gut and in feces excreted into the upper epidermis. Scabies mites feed on epidermal protein, including host plasma; consequently, they are exposed to host defense mechanisms both internally and externally. We found that two recombinantly expressed SMIPPs inhibited all three pathways of the human complement system. Both SMIPPs exerted their inhibitory action due to binding of three molecules involved in the three different mechanisms which initiate complement: C1q, mannose-binding lectin, and properdin. Both SMIPPs bound to the stalk domains of C1q, possibly displacing or inhibiting C1r/C1s, which are associated with the same domain. Furthermore, we found that binding of both SMIPPs to properdin resulted in prevention of assembly of the alternative pathway convertases. However, the SMIPPs were not able to dissociate already formed convertases. Immunohistochemical staining demonstrated the presence of C1q in the gut of scabies mites in skin burrows. We propose that SMIPPs minimize complement-mediated gut damage and thus create a favorable environment for the scabies mites.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by Program Grant 496600 and a fellowship to D.J.K. from the Australian National Health and Medical Research Council and by grants from the Swedish Research Council, Swedish Foundation for Strategic Research, Foundations of Österlund, Kock, King Gustav V’s 80th Anniversary Foundation, Knut and Alice Wallenberg, Inga-Britt and Arne Lundberg, and research grants from the University Hospitals in Malmö.
2 F.C.B., S.R., K.F., and A.M.B. contributed equally to the study.
3 Address correspondence and reprint requests to Dr. Anna M. Blom, Department of Laboratory Medicine, Medical Protein Chemistry, The Wallenberg Laboratory, Floor 4, University Hospital Malmö entrance 46, Lund University, SE-205 02 Malmö, Sweden. E-mail: anna.blom{at}med.lu.se
4 Abbreviations used in this paper: MBL, mannose-binding lectin; C4BP, C4b-binding protein; HDM, house dust mite; NHS, normal human serum; SMIPP, scabies mite inactivated protease paralog; RT, room temperature; MES, 2-(N-morpholino)ethanesulfonic acid.
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