title: Scabies mite inactivated serine protease paralogs inhibit the human complement system.
abstract: 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.
authors.affiliation: Department of Laboratory Medicine, Wallenberg Laboratory, University Hospital Malmö, Lund University, Malmö, Sweden.
authors.forename: Frida C
authors.initials: FC
authors.lastname: Bergström
authors.forename: Simone
authors.initials: S
authors.lastname: Reynolds
authors.forename: Masego
authors.initials: M
authors.lastname: Johnstone
authors.forename: Robert N
authors.initials: RN
authors.lastname: Pike
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Buckle
authors.forename: David J
authors.initials: DJ
authors.lastname: Kemp
authors.forename: Katja
authors.initials: K
authors.lastname: Fischer
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blom
mesh_terms: D000818:Animals; D003165:Complement System Proteins / Q000276:immunology*; D004789:Enzyme Activation; D006461:Hemolysis; D006801:Humans; D011485:Protein Binding; D012520:Sarcoptes scabiei / Q000201:enzymology*; D012532:Scabies / Q000276:immunology* / Q000473:pathology; D012697:Serine Endopeptidases / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D012756:Sheep
chemical_list: D003165:Complement System Proteins; D012697:Serine Endopeptidases