{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T15:21:14Z","timestamp":1790695274345,"version":"4.1.0"},"reference-count":49,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2020,12,2]],"date-time":"2020-12-02T00:00:00Z","timestamp":1606867200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Institut Pasteur \u201cMicrobes & Brain\u201d"},{"DOI":"10.13039\/501100019122","name":"Fondation Raoul Follereau","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100019122","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"French Government\u2019s Investissement d\u2019Avenir program","doi-asserted-by":"publisher","award":["ANR-10-LABX-62-IBEID"],"award-info":[{"award-number":["ANR-10-LABX-62-IBEID"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"Laboratoire d\u2019Excellence \"Integrative Biology of Emerging Infectious Diseases\"","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:p><jats:italic>Mycobacterium ulcerans<\/jats:italic>, the causative agent of Buruli ulcer (BU) disease, is unique amongst human pathogens in its capacity to produce a lipid toxin called mycolactone. While previous studies have demonstrated that bacterially-released mycolactone diffuses beyond infection foci, the spatiotemporal distribution of mycolactone remained largely unknown. Here, we used the zebrafish model to provide the first global kinetic analysis of mycolactone\u2019s diffusion <jats:italic>in vivo<\/jats:italic>, and multicellular co-culture systems to address the critical question of the toxin\u2019s access to the brain.<\/jats:p>\n<jats:p>Zebrafish larvae were injected with a fluorescent-derivative of mycolactone to visualize the <jats:italic>in vivo<\/jats:italic> diffusion of the toxin from the peripheral circulation. A rapid, body-wide distribution of mycolactone was observed, with selective accumulation in tissues near the injection site and brain, together with an important excretion through the gastro-intestinal tract. Our conclusion that mycolactone reached the central nervous system was reinforced by an <jats:italic>in cellulo<\/jats:italic> model of human blood brain barrier and a mouse model of <jats:italic>M<\/jats:italic>. <jats:italic>ulcerans<\/jats:italic>-infection.<\/jats:p>\n<jats:p>Here we show that mycolactone has a broad but heterogenous profile of distribution <jats:italic>in vivo<\/jats:italic>. Our investigations <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> support the view that a fraction of bacterially-produced mycolactone gains access to the central nervous system. The relative persistence of mycolactone in the bloodstream suggests that assays of circulating mycolactone are relevant for BU disease monitoring and treatment optimization.<\/jats:p>","DOI":"10.1371\/journal.pntd.0008878","type":"journal-article","created":{"date-parts":[[2020,12,2]],"date-time":"2020-12-02T18:40:13Z","timestamp":1606934413000},"page":"e0008878","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["Spatiotemporal analysis of mycolactone distribution in vivo reveals partial diffusion in the central nervous system"],"prefix":"10.1371","volume":"14","author":[{"given":"Emma","family":"Colucci-Guyon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aline","family":"Rifflet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Saint-Auret","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana\u00eblle","family":"da Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Boucontet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9359-2783","authenticated-orcid":true,"given":"Thomas","family":"Laval","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9183-4649","authenticated-orcid":true,"given":"Christophe","family":"Prehaud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3097-0548","authenticated-orcid":true,"given":"Nicolas","family":"Blanchard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6775-2416","authenticated-orcid":true,"given":"Jean-Pierre","family":"Levraud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8122-509X","authenticated-orcid":true,"given":"Ivo G.","family":"Boneca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7848-586X","authenticated-orcid":true,"given":"Caroline","family":"Demangel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9791-5308","authenticated-orcid":true,"given":"Laure","family":"Guenin-Mac\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2020,12,2]]},"reference":[{"key":"pntd.0008878.ref001","doi-asserted-by":"crossref","first-page":"e0006058","DOI":"10.1371\/journal.pntd.0006058","article-title":"Mycolactone displays anti-inflammatory effects on the nervous system","volume":"11","author":"C Isaac","year":"2017","journal-title":"PLoS Negl Trop Dis"},{"key":"pntd.0008878.ref002","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1126\/science.283.5403.854","article-title":"Mycolactone: a polyketide toxin from Mycobacterium ulcerans required for virulence","volume":"283","author":"KM George","year":"1999","journal-title":"Science"},{"key":"pntd.0008878.ref003","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/978-3-030-11114-4_7","volume-title":"Buruli Ulcer: Mycobacterium Ulcerans Disease","author":"L Guenin-Mac\u00e9","year":"2019"},{"key":"pntd.0008878.ref004","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1039\/c3np70068b","article-title":"History, biology and chemistry of Mycobacterium ulcerans infections (Buruli ulcer disease)","volume":"30","author":"A-C Chany","year":"2013","journal-title":"Nat Prod Rep"},{"key":"pntd.0008878.ref005","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/nrmicro2077","article-title":"Buruli ulcer: reductive evolution enhances pathogenicity of Mycobacterium ulcerans","volume":"7","author":"C Demangel","year":"2009","journal-title":"Nat Rev Microbiol"},{"key":"pntd.0008878.ref006","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.1086\/646615","article-title":"Immunosuppressive signature of cutaneous Mycobacterium ulcerans infection in the peripheral blood of patients with buruli ulcer disease","volume":"200","author":"R Phillips","year":"2009","journal-title":"J Infect Dis"},{"key":"pntd.0008878.ref007","doi-asserted-by":"crossref","first-page":"e1237","DOI":"10.1371\/journal.pntd.0001237","article-title":"Mycolactone diffuses into the peripheral blood of Buruli ulcer patients\u2014implications for diagnosis and disease monitoring","volume":"5","author":"FS Sarfo","year":"2011","journal-title":"PLoS Negl Trop Dis"},{"key":"pntd.0008878.ref008","doi-asserted-by":"crossref","first-page":"e325","DOI":"10.1371\/journal.pntd.0000325","article-title":"Mycolactone diffuses from Mycobacterium ulcerans-infected tissues and targets mononuclear cells in peripheral blood and lymphoid organs","volume":"2","author":"H Hong","year":"2008","journal-title":"PLoS Negl Trop Dis"},{"key":"pntd.0008878.ref009","doi-asserted-by":"crossref","first-page":"1404","DOI":"10.1242\/jcs.182352","article-title":"Mechanistic insights into the inhibition of Sec61-dependent co- and post-translational translocation by mycolactone","volume":"129","author":"M McKenna","year":"2016","journal-title":"J Cell Sci"},{"key":"pntd.0008878.ref010","doi-asserted-by":"crossref","first-page":"2885","DOI":"10.1084\/jem.20160662","article-title":"Mycolactone subverts immunity by selectively blocking the Sec61 translocon","volume":"213","author":"L Baron","year":"2016","journal-title":"J Exp Med"},{"key":"pntd.0008878.ref011","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1042\/BST20130133","article-title":"Pleiotropic molecular effects of the Mycobacterium ulcerans virulence factor mycolactone underlying the cell death and immunosuppression seen in Buruli ulcer","volume":"42","author":"B Hall","year":"2014","journal-title":"Biochemical Society Transactions"},{"key":"pntd.0008878.ref012","doi-asserted-by":"crossref","first-page":"289ra85","DOI":"10.1126\/scitranslmed.aab0458","article-title":"Shaping mycolactone for therapeutic use against inflammatory disorders","volume":"7","author":"L Guenin-Mac\u00e9","year":"2015","journal-title":"Sci Transl Med"},{"key":"pntd.0008878.ref013","article-title":"Sec61 blockade by mycolactone: A central mechanism in Buruli ulcer disease","author":"C Demangel","year":"2018","journal-title":"Biol Cell"},{"key":"pntd.0008878.ref014","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/s41419-018-0427-y","article-title":"Inhibition of Sec61-dependent translocation by mycolactone uncouples the integrated stress response from ER stress, driving cytotoxicity via translational activation of ATF4","volume":"9","author":"J Ogbechi","year":"2018","journal-title":"Cell Death Dis"},{"key":"pntd.0008878.ref015","first-page":"6","article-title":"Zebrafish as an Emerging Model for Bioassay-Guided Natural Product Drug Discovery for Neurological Disorders","author":"A Pitchai","year":"2019","journal-title":"Medicines (Basel)"},{"key":"pntd.0008878.ref016","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/nrd1606","article-title":"In vivo drug discovery in the zebrafish","volume":"4","author":"LI Zon","year":"2005","journal-title":"Nat Rev Drug Discov"},{"key":"pntd.0008878.ref017","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1038\/nature12111","article-title":"The zebrafish reference genome sequence and its relationship to the human genome","volume":"496","author":"K Howe","year":"2013","journal-title":"Nature"},{"key":"pntd.0008878.ref018","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.tim.2019.08.005","article-title":"The Case for Modeling Human Infection in Zebrafish","volume":"28","author":"MC Gomes","year":"2020","journal-title":"Trends Microbiol"},{"key":"pntd.0008878.ref019","doi-asserted-by":"crossref","first-page":"e663","DOI":"10.1371\/journal.pntd.0000663","article-title":"Mycobacterium ulcerans and Other Mycolactone-Producing Mycobacteria Should Be Considered a Single Species","volume":"4","author":"SJ Pidot","year":"2010","journal-title":"PLOS Neglected Tropical Diseases"},{"key":"pntd.0008878.ref020","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.micinf.2012.02.009","article-title":"Mycobacterium ulcerans causes minimal pathogenesis and colonization in Medaka (Oryzias latipes): An experimental fish model of disease transmission","volume":"14","author":"L Mosi","year":"2012","journal-title":"Microbes Infect"},{"key":"pntd.0008878.ref021","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.phrs.2017.08.017","article-title":"Zebrafish: A promising in vivo model for assessing the delivery of natural products, fluorescence dyes and drugs across the blood-brain barrier","volume":"125","author":"Y Li","year":"2017","journal-title":"Pharmacol Res"},{"key":"pntd.0008878.ref022","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1101\/gad.309823.117","article-title":"Bridging barriers: a comparative look at the blood-brain barrier across organisms","volume":"32","author":"NM O\u2019Brown","year":"2018","journal-title":"Genes Dev"},{"key":"pntd.0008878.ref023","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.ydbio.2019.03.005","article-title":"Development of the brain vasculature and the blood-brain barrier in zebrafish","volume":"457","author":"C Qui\u00f1onez-Silvero","year":"2020","journal-title":"Dev Biol"},{"key":"pntd.0008878.ref024","doi-asserted-by":"crossref","first-page":"14413","DOI":"10.1002\/chem.201102542","article-title":"A diverted total synthesis of mycolactone analogues: an insight into buruli ulcer toxins","volume":"17","author":"AC Chany","year":"2011","journal-title":"Chemistry"},{"key":"pntd.0008878.ref025","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1172\/JCI66576","article-title":"Mycolactone activation of Wiskott-Aldrich syndrome proteins underpins Buruli ulcer formation","volume":"123","author":"L Guenin-Mace","year":"2013","journal-title":"The Journal of Clinical Investigation"},{"key":"pntd.0008878.ref026","doi-asserted-by":"crossref","first-page":"7382","DOI":"10.1021\/jm5008819","article-title":"Synthetic variants of mycolactone bind and activate Wiskott-Aldrich syndrome proteins","volume":"57","author":"AC Chany","year":"2014","journal-title":"J Med Chem"},{"key":"pntd.0008878.ref027","doi-asserted-by":"crossref","first-page":"1410","DOI":"10.1039\/b924896j","article-title":"Highly sensitive, operationally simple, cost\/time effective detection of the mycolactones from the human pathogen Mycobacterium ulcerans","volume":"46","author":"T Spangenberg","year":"2010","journal-title":"Chem Commun (Camb)"},{"key":"pntd.0008878.ref028","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1101\/gad.1629408","article-title":"Foxn4 directly regulates tbx2b expression and atrioventricular canal formation","volume":"22","author":"NC Chi","year":"2008","journal-title":"Genes Dev"},{"key":"pntd.0008878.ref029","doi-asserted-by":"crossref","first-page":"e1007157","DOI":"10.1371\/journal.ppat.1007157","article-title":"Neutrophils use superoxide to control bacterial infection at a distance","volume":"14","author":"QT Phan","year":"2018","journal-title":"PLoS Pathog"},{"key":"pntd.0008878.ref030","volume-title":"The Zebrafish Book. A Guide for the Laboratory Use of Zebrafish (Danio rerio)","author":"M Westerfield","year":"2000"},{"key":"pntd.0008878.ref031","doi-asserted-by":"crossref","first-page":"3053","DOI":"10.1242\/jcs.082792","article-title":"Strategies of professional phagocytes in vivo: unlike macrophages, neutrophils engulf only surface-associated microbes","volume":"124","author":"E Colucci-Guyon","year":"2011","journal-title":"J Cell Sci"},{"key":"pntd.0008878.ref032","doi-asserted-by":"crossref","first-page":"e1003588","DOI":"10.1371\/journal.ppat.1003588","article-title":"The zebrafish as a new model for the in vivo study of Shigella flexneri interaction with phagocytes and bacterial autophagy","volume":"9","author":"S Mostowy","year":"2013","journal-title":"PLoS Pathog"},{"key":"pntd.0008878.ref033","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.3389\/fimmu.2018.01084","article-title":"A Model of Superinfection of Virus-Infected Zebrafish Larvae: Increased Susceptibility to Bacteria Associated With Neutrophil Death","volume":"9","author":"L Boucontet","year":"2018","journal-title":"Front Immunol"},{"key":"pntd.0008878.ref034","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1182\/blood-2007-06-095398","article-title":"Origins and unconventional behavior of neutrophils in developing zebrafish","volume":"111","author":"D Le Guyader","year":"2008","journal-title":"Blood"},{"key":"pntd.0008878.ref035","doi-asserted-by":"crossref","first-page":"8375","DOI":"10.1038\/ncomms9375","article-title":"NACA deficiency reveals the crucial role of somite-derived stromal cells in haematopoietic niche formation","volume":"6","author":"E Murayama","year":"2015","journal-title":"Nat Commun"},{"key":"pntd.0008878.ref036","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1038\/nmeth.2075","article-title":"Icy: an open bioimage informatics platform for extended reproducible research","volume":"9","author":"F de Chaumont","year":"2012","journal-title":"Nat Methods"},{"key":"pntd.0008878.ref037","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/2045-8118-10-16","article-title":"The hCMEC\/D3 cell line as a model of the human blood brain barrier","volume":"10","author":"B Weksler","year":"2013","journal-title":"Fluids Barriers CNS"},{"key":"pntd.0008878.ref038","article-title":"A Human Blood-Brain Interface Model to Study Barrier Crossings by Pathogens or Medicines and Their Interactions with the Brain","author":"A da Costa","year":"2019","journal-title":"J Vis Exp"},{"key":"pntd.0008878.ref039","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.biologicals.2018.03.004","article-title":"Innovative in cellulo method as an alternative to in vivo neurovirulence test for the characterization and quality control of human live Yellow Fever virus vaccines: A pilot study","volume":"53","author":"A da Costa","year":"2018","journal-title":"Biologicals"},{"key":"pntd.0008878.ref040","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1002\/jcp.1041320115","article-title":"Molecular sieving characteristics of the cultured endothelial monolayer","volume":"132","author":"A Siflinger-Birnboim","year":"1987","journal-title":"J Cell Physiol"},{"key":"pntd.0008878.ref041","doi-asserted-by":"crossref","first-page":"e10777","DOI":"10.1371\/journal.pone.0010777","article-title":"Optimisation of bioluminescent reporters for use with mycobacteria","volume":"5","author":"N Andreu","year":"2010","journal-title":"PLoS ONE"},{"key":"pntd.0008878.ref042","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1101\/gad.1629408","article-title":"Foxn4 directly regulates tbx2b expression and atrioventricular canal formation","volume":"22","author":"NC Chi","year":"2008","journal-title":"Genes Dev"},{"key":"pntd.0008878.ref043","doi-asserted-by":"crossref","first-page":"6752","DOI":"10.1021\/jm901241e","article-title":"Escape from flatland: increasing saturation as an approach to improving clinical success","volume":"52","author":"F Lovering","year":"2009","journal-title":"J Med Chem"},{"key":"pntd.0008878.ref044","doi-asserted-by":"crossref","first-page":"2138","DOI":"10.1021\/acsnano.7b06995","article-title":"Directing Nanoparticle Biodistribution through Evasion and Exploitation of Stab2-Dependent Nanoparticle Uptake","volume":"12","author":"F Campbell","year":"2018","journal-title":"ACS Nano"},{"key":"pntd.0008878.ref045","first-page":"7","article-title":"Quantitating the subtleties of microglial morphology with fractal analysis","author":"A Karperien","year":"2013","journal-title":"Front Cell Neurosci"},{"key":"pntd.0008878.ref046","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1128\/IAI.66.2.587-593.1998","article-title":"Partial purification and characterization of biological effects of a lipid toxin produced by Mycobacterium ulcerans","volume":"66","author":"KM George","year":"1998","journal-title":"Infect Immun"},{"key":"pntd.0008878.ref047","doi-asserted-by":"crossref","first-page":"2194","DOI":"10.4049\/jimmunol.0802294","article-title":"Mycolactone inhibits monocyte cytokine production by a posttranscriptional mechanism","volume":"182","author":"RE Simmonds","year":"2009","journal-title":"J Immunol"},{"key":"pntd.0008878.ref048","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.4269\/ajtmh.18-0959","article-title":"In Vivo Imaging of Bioluminescent Mycobacterium ulcerans: A Tool to Refine the Murine Buruli Ulcer Tail Model","volume":"101","author":"TF Omansen","year":"2019","journal-title":"Am J Trop Med Hyg"},{"key":"pntd.0008878.ref049","first-page":"11","article-title":"Understanding the Significance of Biochemistry in the Storage, Handling, Purification, and Sampling of Amphiphilic Mycolactone","author":"JZ Kubicek-Sutherland","year":"2019","journal-title":"Toxins (Basel)"}],"container-title":["PLOS Neglected Tropical Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0008878","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,12,2]],"date-time":"2020-12-02T18:40:31Z","timestamp":1606934431000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0008878"}},"subtitle":[],"editor":[{"given":"Paul J.","family":"Converse","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2020,12,2]]},"references-count":49,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,12,2]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pntd.0008878","relation":{},"ISSN":["1935-2735"],"issn-type":[{"value":"1935-2735","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,2]]}}}