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Spatiotemporal analysis of mycolactone distribution in vivo reveals partial diffusion in the central nervous system

Mycobacterium ulcerans, 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 d...

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Autores principales: Colucci-Guyon, Emma, Rifflet, Aline, Saint-Auret, Sarah, da Costa, Anaëlle, Boucontet, Laurent, Laval, Thomas, Prehaud, Christophe, Blanchard, Nicolas, Levraud, Jean-Pierre, Boneca, Ivo G., Demangel, Caroline, Guenin-Macé, Laure
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710047/
https://www.ncbi.nlm.nih.gov/pubmed/33264290
http://dx.doi.org/10.1371/journal.pntd.0008878
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author Colucci-Guyon, Emma
Rifflet, Aline
Saint-Auret, Sarah
da Costa, Anaëlle
Boucontet, Laurent
Laval, Thomas
Prehaud, Christophe
Blanchard, Nicolas
Levraud, Jean-Pierre
Boneca, Ivo G.
Demangel, Caroline
Guenin-Macé, Laure
author_facet Colucci-Guyon, Emma
Rifflet, Aline
Saint-Auret, Sarah
da Costa, Anaëlle
Boucontet, Laurent
Laval, Thomas
Prehaud, Christophe
Blanchard, Nicolas
Levraud, Jean-Pierre
Boneca, Ivo G.
Demangel, Caroline
Guenin-Macé, Laure
author_sort Colucci-Guyon, Emma
collection PubMed
description Mycobacterium ulcerans, 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’s diffusion in vivo, and multicellular co-culture systems to address the critical question of the toxin’s access to the brain. Zebrafish larvae were injected with a fluorescent-derivative of mycolactone to visualize the in vivo 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 in cellulo model of human blood brain barrier and a mouse model of M. ulcerans-infection. Here we show that mycolactone has a broad but heterogenous profile of distribution in vivo. Our investigations in vitro and in vivo 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.
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spelling pubmed-77100472020-12-03 Spatiotemporal analysis of mycolactone distribution in vivo reveals partial diffusion in the central nervous system Colucci-Guyon, Emma Rifflet, Aline Saint-Auret, Sarah da Costa, Anaëlle Boucontet, Laurent Laval, Thomas Prehaud, Christophe Blanchard, Nicolas Levraud, Jean-Pierre Boneca, Ivo G. Demangel, Caroline Guenin-Macé, Laure PLoS Negl Trop Dis Research Article Mycobacterium ulcerans, 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’s diffusion in vivo, and multicellular co-culture systems to address the critical question of the toxin’s access to the brain. Zebrafish larvae were injected with a fluorescent-derivative of mycolactone to visualize the in vivo 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 in cellulo model of human blood brain barrier and a mouse model of M. ulcerans-infection. Here we show that mycolactone has a broad but heterogenous profile of distribution in vivo. Our investigations in vitro and in vivo 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. Public Library of Science 2020-12-02 /pmc/articles/PMC7710047/ /pubmed/33264290 http://dx.doi.org/10.1371/journal.pntd.0008878 Text en © 2020 Colucci-Guyon et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Colucci-Guyon, Emma
Rifflet, Aline
Saint-Auret, Sarah
da Costa, Anaëlle
Boucontet, Laurent
Laval, Thomas
Prehaud, Christophe
Blanchard, Nicolas
Levraud, Jean-Pierre
Boneca, Ivo G.
Demangel, Caroline
Guenin-Macé, Laure
Spatiotemporal analysis of mycolactone distribution in vivo reveals partial diffusion in the central nervous system
title Spatiotemporal analysis of mycolactone distribution in vivo reveals partial diffusion in the central nervous system
title_full Spatiotemporal analysis of mycolactone distribution in vivo reveals partial diffusion in the central nervous system
title_fullStr Spatiotemporal analysis of mycolactone distribution in vivo reveals partial diffusion in the central nervous system
title_full_unstemmed Spatiotemporal analysis of mycolactone distribution in vivo reveals partial diffusion in the central nervous system
title_short Spatiotemporal analysis of mycolactone distribution in vivo reveals partial diffusion in the central nervous system
title_sort spatiotemporal analysis of mycolactone distribution in vivo reveals partial diffusion in the central nervous system
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710047/
https://www.ncbi.nlm.nih.gov/pubmed/33264290
http://dx.doi.org/10.1371/journal.pntd.0008878
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