Scabies Mite Inactive Serine Proteases Are Potent Inhibitors of the Human Complement Lectin Pathway

Abstract

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.

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).…”

The public health control of scabies: priorities for research and action

“…Scabies mite components such as serpins inhibit innate immune pathways including neutrophil function and directly promote the growth of Staphylococcus aureus and Streptococcus pyogenes. [28][29][30][31] Skin infection due to these bacteria can lead to severe soft tissue infections and invasive disease. Infection with S. pyogenes can also lead to immunemediated complications including post-streptococcal glomerulonephritis and possibly acute rheumatic fever, which in turn contribute to chronic kidney disease and rheumatic heart disease ( Figure 3).…”

Tsetse GmmSRPN10 Has Anti-complement Activity and Is Important for Successful Establishment of Trypanosome Infections in the Fly Midgut

“…Inactivation of both human rC1s and rFactor D, initiating serine proteases of the classical and alternative pathways, respectively [48] , suggests that GmmSRPN10 may have a generic inhibitory function against complement cascade serine proteases. This might be a characteristic of arthropod complement-inhibitory factors, as exhaustive investigation into scabies mite serine proteases (SMB3, SMB4) as well as inactive serine proteases have found them to inhibit all three complement cascade pathways [8] , [49] .…”