Abstract
A well-known histopathological feature of diseased skin in Buruli ulcer (BU) is coagulative necrosis caused by the Mycobacterium ulcerans macrolide exotoxin mycolactone. Since the underlying mechanism is not known, we have investigated the effect of mycolactone on endothelial cells, focussing on the expression of surface anticoagulant molecules involved in the protein C anticoagulant pathway. Congenital deficiencies in this natural anticoagulant pathway are known to induce thrombotic complications such as purpura fulimans and spontaneous necrosis. Mycolactone profoundly decreased thrombomodulin (TM) expression on the surface of human dermal microvascular endothelial cells (HDMVEC) at doses as low as 2ng/ml and as early as 8hrs after exposure. TM activates protein C by altering thrombin’s substrate specificity, and exposure of HDMVEC to mycolactone for 24 hours resulted in an almost complete loss of the cells’ ability to produce activated protein C. Loss of TM was shown to be due to a previously described mechanism involving mycolactone-dependent blockade of Sec61 translocation that results in proteasome-dependent degradation of newly synthesised ER-transiting proteins. Indeed, depletion from cells determined by live-cell imaging of cells stably expressing a recombinant TM-GFP fusion protein occurred at the known turnover rate. In order to determine the relevance of these findings to BU disease, immunohistochemistry of punch biopsies from 40 BU lesions (31 ulcers, nine plaques) was performed. TM abundance was profoundly reduced in the subcutis of 78% of biopsies. Furthermore, it was confirmed that fibrin deposition is a common feature of BU lesions, particularly in the necrotic areas. These findings indicate that there is decreased ability to control thrombin generation in BU skin. Mycolactone’s effects on normal endothelial cell function, including its ability to activate the protein C anticoagulant pathway are strongly associated with this. Fibrin-driven tissue ischemia could contribute to the development of the tissue necrosis seen in BU lesions.
Highlights
The neglected tropical disease Buruli ulcer (BU), caused by subcutaneous infection with Mycobacterium ulcerans, is most common in West Africa, but has reported from Australia and altogether more than 30 countries worldwide [1]
Buruli ulcer (BU) is a neglected tropical disease that is most common in West Africa and parts of Australia, but has been reported from over 30 countries worldwide
We have studied the effects of mycolactone on endothelial cells, specialised cells that line blood vessels and form capillaries
Summary
The neglected tropical disease Buruli ulcer (BU), caused by subcutaneous infection with Mycobacterium ulcerans, is most common in West Africa, but has reported from Australia and altogether more than 30 countries worldwide [1]. These indolent, painless, ulcers affect at least 5,000 patients/year and are thought to be heavily under-reported. Ulcers can extend to 15% of the skin surface area and cause significant morbidity [2]. Adjunct surgical debridement followed by skin grafting is often required for larger lesions [7,8,9]. A therapeutic approach reducing the lesion size could profoundly improve the status quo in BU care
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