{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T15:05:39Z","timestamp":1791990339221,"version":"4.4.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1010280","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,2,15]],"date-time":"2022-02-15T00:00:00Z","timestamp":1644883200000}}],"reference-count":121,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T00:00:00Z","timestamp":1643587200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"wellcome trust","doi-asserted-by":"publisher","award":["202843\/Z\/Z16\/Z"],"award-info":[{"award-number":["202843\/Z\/Z16\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Infectious Disease Research Trust"},{"name":"Medicor Foundation"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Buruli ulcer (BU) is a neglected tropical disease caused by subcutaneous infection with\n                    <jats:italic>Mycobacterium ulcerans<\/jats:italic>\n                    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 \u2018indirect\u2019 route to mycolactone-dependent tissue necrosis by a mechanism involving vascular dysfunction. Here, we tracked &gt;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\u2019s 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\n                    <jats:italic>in vitro<\/jats:italic>\n                    . This was indeed the case, and leakage was further exacerbated by IL-1\u03b2. 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 \u201cleaky\u201d 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.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1010280","type":"journal-article","created":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T13:37:54Z","timestamp":1643636274000},"page":"e1010280","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":17,"title":["Aberrant stromal tissue factor localisation and mycolactone-driven vascular dysfunction, exacerbated by IL-1\u03b2, are linked to fibrin formation in Buruli ulcer lesions"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9499-889X","authenticated-orcid":true,"given":"Louise Tzung-Harn","family":"Hsieh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7793-3501","authenticated-orcid":true,"given":"Scott J.","family":"Dos Santos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belinda S.","family":"Hall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5924-7647","authenticated-orcid":true,"given":"Joy","family":"Ogbechi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7179-8799","authenticated-orcid":true,"given":"Aloysius D.","family":"Loglo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5315-3882","authenticated-orcid":true,"given":"Francisco Javier","family":"Salguero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6512-5515","authenticated-orcid":true,"given":"Marie-Th\u00e9r\u00e8se","family":"Ruf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1957-2925","authenticated-orcid":true,"given":"Gerd","family":"Pluschke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4843-8266","authenticated-orcid":true,"given":"Rachel E.","family":"Simmonds","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,1,31]]},"reference":[{"key":"ppat.1010280.ref001","volume-title":"Situation and trends","author":"WHO BU","year":"2019"},{"issue":"7","key":"ppat.1010280.ref002","doi-asserted-by":"crossref","first-page":"e912","DOI":"10.1016\/S2214-109X(19)30171-8","article-title":"Mapping the global distribution of Buruli ulcer: a systematic review with evidence consensus","volume":"7","author":"H Simpson","year":"2019","journal-title":"Lancet Glob Health"},{"key":"ppat.1010280.ref003","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/978-3-030-11114-4_3","volume-title":"Buruli Ulcer: Mycobacterium Ulcerans Disease","author":"PDR Johnson","year":"2019"},{"issue":"4","key":"ppat.1010280.ref004","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/s40475-018-0166-2","article-title":"Buruli Ulcer: a Review of the Current Knowledge","volume":"5","author":"RR Yotsu","year":"2018","journal-title":"Curr Trop Med Rep"},{"key":"ppat.1010280.ref005","first-page":"752749","article-title":"Buruli-ulcer induced disability in ghana: a study at apromase in the ashanti 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Marion","year":"2014","journal-title":"Cell"},{"issue":"6","key":"ppat.1010280.ref029","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1182\/blood-2018-07-818211","article-title":"The multifaceted role of fibrinogen in tissue injury and inflammation","volume":"133","author":"JP Luyendyk","year":"2019","journal-title":"Blood"},{"issue":"5","key":"ppat.1010280.ref030","doi-asserted-by":"crossref","first-page":"e0124446","DOI":"10.1371\/journal.pone.0124446","article-title":"Diabetic foot complications and their risk factors from a large retrospective cohort study","volume":"10","author":"K Al-Rubeaan","year":"2015","journal-title":"PLoS One"},{"issue":"1","key":"ppat.1010280.ref031","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1177\/1358836X0000500108","article-title":"The endothelium: a new target for therapy","volume":"5","author":"JP Cooke","year":"2000","journal-title":"Vasc 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