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Mycolactone-Dependent Depletion of Endothelial Cell Thrombomodulin Is Strongly Associated with Fibrin Deposition in Buruli Ulcer Lesions.

Ogbechi, J, Ruf, MT, Hall, BS, Bodman-Smith, K, Vogel, M, Wu, HL, Stainer, A, Esmon, CT, Ahnström, J, Pluschke, G and Simmonds, RE (2015) Mycolactone-Dependent Depletion of Endothelial Cell Thrombomodulin Is Strongly Associated with Fibrin Deposition in Buruli Ulcer Lesions. PLoS Pathog, 11 (7).

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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.

Item Type: Article
Divisions : Faculty of Health and Medical Sciences > School of Biosciences and Medicine > Department of Microbial and Cellular Sciences
Authors :
AuthorsEmailORCID
Ogbechi, JUNSPECIFIEDUNSPECIFIED
Ruf, MTUNSPECIFIEDUNSPECIFIED
Hall, BSUNSPECIFIEDUNSPECIFIED
Bodman-Smith, KUNSPECIFIEDUNSPECIFIED
Vogel, MUNSPECIFIEDUNSPECIFIED
Wu, HLUNSPECIFIEDUNSPECIFIED
Stainer, AUNSPECIFIEDUNSPECIFIED
Esmon, CTUNSPECIFIEDUNSPECIFIED
Ahnström, JUNSPECIFIEDUNSPECIFIED
Pluschke, GUNSPECIFIEDUNSPECIFIED
Simmonds, REUNSPECIFIEDUNSPECIFIED
Date : July 2015
Identification Number : 10.1371/journal.ppat.1005011
Related URLs :
Additional Information : © 2015 Ogbechi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, p
Depositing User : Symplectic Elements
Date Deposited : 29 Sep 2015 18:05
Last Modified : 29 Sep 2015 18:05
URI: http://epubs.surrey.ac.uk/id/eprint/808485

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