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.

A Proteomic Analysis ofSarcoptes scabiei(Acari: Sarcoptidae)

“…Previous studies have used aqueous extracts of scabies mite whole body homogenates to demonstrate that these mites are the sources of many antigenic and allergenic proteins (Arlian et al 1988a(Arlian et al , 1991(Arlian et al , 1996b(Arlian et al , 2004aMorgan and Arlian 1994;Morgan et al 1997;Arlian and Morgan 2000;Schumann et al 2001) as well as to demonstrate that these mites produce molecules that are able to modulate the immune response of an infested host (Arlian et al 1996c(Arlian et al , 2003(Arlian et al , 2004a(Arlian et al , 2007Elder et al 2006Elder et al , 2009Lalli et al 2004;Bergstrom et al 2009;Arlian 2009, 2010;Mullins et al 2009;Mika et al 2012;Morgan et al 2013;Reynolds et al 2014;Swe and Fischer 2014). The molecules responsible for the observed antigenic and immunomodulatory activities of scabies mite extracts have not been identified.…”

“…It must find a host, penetrate and burrow in the stratum corneum of the epidermis to obtain nutrients and shelter, and the sexes must find each other and mate so that females can produce eggs in order to establish a population in the host all the while avoiding elimination by the host's protective innate and humoral immune responses. Although the mites provoke a defensive response by the host, they are the sources of molecules that down-modulate the initial innate and humoral responses, presumably allowing the mites to survive, reproduce, and establish a population in the host skin (Arlian et al 1996c(Arlian et al , 2003(Arlian et al , 2004b(Arlian et al , 2007Elder et al 2006Elder et al , 2009Lalli et al 2004;Arlian 2009, 2010;Bergstrom et al 2009;Mullins et al 2009;Mika et al 2012;Morgan et al 2013;Reynolds et al 2014;Swe and Fischer 2014).…”

Increased Allergic Immune Response toSarcoptes scabieiAntigens in Crusted versus Ordinary Scabies

“…The cloning of SM proteins corresponding to those of the predominant HDM allergens has now facilitated studies of their sequence homology (25,26,34,45,46,49,50), localization (47,51), enzymatic activity (7,16,22,35,40), and interactions with the immune system (8,11,30). Here, we have studied differences in the types and magnitudes of the systemic antibody and cellular responses to characterize the specific immune response in OS and compare it to the more severe and debilitating crusted form of the disease (CS).…”

Proteases as therapeutics

“…An exception is HGF (hepatocyte growth factor), which has a trypsin fold but lacks any of the three catalytic residues typical of a protease of this type, that has a clear role in cell signalling and proliferation [10]. Several HGF-like proteins are found in our genome and inactive trypsins are found in abundance in the insect genomes [11]. Protease-dependent processes include digestion, protein processing, homoeostasis, development, apoptosis, protein turnover, immunity, complement activation, blood coagulation and many others.…”