A unique group of scabies mite pseudoproteases promotes cutaneous blood coagulation and delays plasmin-induced fibrinolysis

Author summary Skin-burrowing scabies mites cause pathological changes in the skin. Although these parasites burrow only down to the border between the epidermis and dermis, fibrin thrombi within the dermal vessels are frequently seen in scabies infected skin. Their origin had been unknown. We show by immunohistology that a unique family of mite proteins, the SMIPP-Cs, is found within these fibrin thrombi. We further demonstrate that the SMIPP-Cs promote blood coagulation, change the structure and density of fibrin clots and make them resistant to fibrinolysis. This may be a novel mechanism by which scabies mites maintain themselves in the microenvironment of the skin. They reside in the lower epidermis close to the dermis to ensure their nutritional requirements are met, and are thereby exposed to the inflammatory and immune responses delivered into the epidermis with the interstitial fluid. To defend themselves from the host immune system the mites release anti-inflammatory, immunosuppressive and, we propose, hemostasis-modulating novel proteins into their microenvironment. Only the scabies mites have evolved the SMIPP-Cs, which appear to play essential roles in the parasitic lifestyle. SMIPP-Cs may present a novel diagnostic or therapeutic target. Background Scabies, a highly contagious skin disease affecting more than 200 million people worldwide at any time, is caused by the parasitic mite Sarcoptes scabiei. In the absence of molecular markers, diagnosis requires experience making surveillance and control challenging. Superficial microthrombi in the absence of vasculitis in scabies-affected skin are a recognised, yet unexplained histopathological differential of scabies infection. This study demonstrates that a family of Scabies Mite Inactivated Cysteine Protease Paralogues (SMIPP-Cs) excreted by the mites plays a role in formation of scabies-induced superficial microthrombi. Methodology/Principal findings A series of in vitro and ex vivo experiments involving two representative recombinant SMIPP-Cs was carried out. In the presence of SMIPP-Cs, the thrombin clotting time (TCT), fibrin formation and plasmin induced fibrinolysis were monitored in vitro. The ultrastructure of the SMIPP-C-modulated fibrin was analysed by Scanning Electron Microscopy (SEM). Immuno-histological analyses were performed ex vivo, to localise the SMIPP-C proteins within scabies infected skin biopsies. SMIPP-Cs displayed pro-coagulant properties. They bound calcium ions, reduced the thrombin clotting time, enhanced the fibrin formation rate and delayed plasmin-induced fibrinolysis. The SMIPP-Cs associated with fibrin clots during fibrinogen polymerisation and did not bind to preformed fibrin. Scanning electron microscopy revealed that the fibrin clots formed in the presence of SMIPP-Cs were aberrant and denser than normal fibrin clots. SMIPP-Cs were detected in microthrombi which are commonly seen in scabietic skin. Conclusions/Significance The SMIPP-Cs are the first scabies mite proteins found in sub-epidermal skin layers and their pro-coagulant properties promote superficial microthrombi formation in scabetic skin. Further research is needed to evaluate their potential as diagnostic or therapeutic target.