Abstract
Buruli ulcer (BU) is a neglected tropical disease caused by subcutaneous infection with Mycobacterium ulcerans and its exotoxin mycolactone. BU displays coagulative necrosis and widespread fibrin deposition in affected skin tissues. Despite this, the role of the vasculature in BU pathogenesis remains almost completely unexplored. We hypothesise that fibrin-driven ischemia can be an ‘indirect’ route to mycolactone-dependent tissue necrosis by a mechanism involving vascular dysfunction. Here, we tracked >900 vessels within contiguous tissue sections from eight BU patient biopsies. Our aim was to evaluate their vascular and coagulation biomarker phenotype and explore potential links to fibrin deposition. We also integrated this with our understanding of mycolactone’s mechanism of action at Sec61 and its impact on proteins involved in maintaining normal vascular function. Our findings showed that endothelial cell dysfunction is common in skin tissue adjacent to necrotic regions. There was little evidence of primary haemostasis, perhaps due to mycolactone-dependent depletion of endothelial von Willebrand factor. Instead, fibrin staining appeared to be linked to the extrinsic pathway activator, tissue factor (TF). There was significantly greater than expected fibrin staining around vessels that had TF staining within the stroma, and this correlated with the distance it extended from the vessel basement membrane. TF-induced fibrin deposition in these locations would require plasma proteins outside of vessels, therefore we investigated whether mycolactone could increase vascular permeability in vitro. This was indeed the case, and leakage was further exacerbated by IL-1β. Mycolactone caused the loss of endothelial adherens and tight junctions by the depletion of VE-cadherin, TIE-1, TIE-2 and JAM-C; all Sec61-dependent proteins. Taken together, our findings suggest that both vascular and lymphatic vessels in BU lesions become “leaky” during infection, due to the unique action of mycolactone, allowing TF-containing structures and plasma proteins into skin tissue, ultimately leading to local coagulopathy and tissue ischemia.
Highlights
Buruli ulcer (BU) is a neglected tropical disease found in over 30 countries world-wide resulting from a subcutaneous infection with Mycobacterium ulcerans, an opportunistic environmental pathogen
We previously found evidence that the vascular system is disrupted by mycolactone in these lesions, and we have further explored potential explanations for these findings by looking at the expression of vascular markers in BU
Mycolactone is able to disrupt the barrier function of the endothelium, further aggravating the diseased phenotype, which may explain how clotting factors access the tissue. Such localised hypercoagulation in Buruli ulcer skin lesions may contribute to the development of the lesion
Summary
Buruli ulcer (BU) is a neglected tropical disease found in over 30 countries world-wide resulting from a subcutaneous infection with Mycobacterium ulcerans, an opportunistic environmental pathogen. According to the World Health Organization (WHO), approximately 2700 new cases were reported globally in 2018 [1], which suggests case numbers are falling from a peak of 5,000–6,000 per year in 2004–2010. Despite its relative rarity globally, BU is a devastating disease in communities with high endemicity, where the prevalence can be up to 77 cases per 10,000 population [2–4]. BU often presents late, due to the characteristic painlessness of the lesions and lack of other overt signs of infection such as fever and malaise. In these patients, necrotic skin ulcers and soft tissue destruction can extend up to 15% of body surface area. To achieve the long-term goal of reducing the disease burden and serious sequelae, there is a real need for a better understanding of BU pathogenesis
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