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Mycolactone: Lipid-Like Immunosuppressive Toxin of Buruli Ulcer

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A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Bacterial Toxins".

Deadline for manuscript submissions: closed (30 June 2019) | Viewed by 22819

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Special Issue Editors

Prof. Dr. Gerd Pluschke

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Guest Editor

Head Molecular Immunology, Swiss Tropical Institute, 4052 Basel, Switzerland

Dr. Rachel Simmonds

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Guest Editor

Department of Microbial Sciences, University of Surrey, Guildford, Surrey GU2 7XH, United Kingdom

Special Issue Information

Dear Colleagues,

Mycobacterium ulcerans is the causative agent of the neglected tropical skin disease, Buruli ulcer (BU). In BU lesions, extracellular clusters of acid-fast bacilli are found in completely necrotic subcutaneous fat tissue. Mycolactone, a polyketide lactone exotoxin is the major virulence factor of M. ulcerans and causes immunosuppression and apoptosis in mammalian cells. Several mammalian molecular targets for mycolactone have been proposed and their relative contributions to the different effects of mycolactone has remained controversial. However, genetic evidence has proven that the Sec61 translocon is a major molecular target of mycolactone and that Bim-dependent apoptosis is crucial for the chronic necrotizing nature of BU. The Sec61 translocon is a molecular machine at the ER membrane with an essential role in the export of many secretory and membrane proteins. Translocation blockade seems to play a key role in mycolactone-mediated immunosuppression and cell death. Mycolactone specific antibodies have been shown to neutralize the toxic activity of mycolactone and may have potential for diagnostic assay development and immune prophylaxis.

The aim of this Special Issue is to draw together the recent advances in our understanding of mycolactone activity and how this impacts BU pathogenesis. Moreover, this Special Issue wishes to highlight the broader implications of mycolactone’s biological activity, with applications in other areas, such as the understanding of translocation biology, cell death pathways and neuroinflammation. We invite original research papers, reviews, short communications, commentaries, and letters to the editor on any topic related to mycolactone including:

Discovery of mycolactone
Buruli ulcer pathogenesis
Anti-inflammatory and immunosuppressive activity
Mycolactone and coagulation control/endothelial dysfunction
Effect on neurons and analgesic properties
Mechanisms of cell death
Biochemistry of translocation inhibition
Potential role of mycolactone in Buruli ulcer transmission
Enzymology and genetics of mycolactone production by M. ulcerans
Immunology of mycolactone and implications for tool development
Mycolactone, BU diagnosis and monitoring of treatment
Chemistry/synthesis of mycolactones
Biophysical properties of mycolactone

Prof. Dr. Gerd Pluschke
Dr. Rachel Simmonds
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Mycobacterium ulcerans
Mycolactone
Buruli ulcer
Pathogenesis
Apoptosis
Protein Translocation
Molecular mechanisms
Polyketide synthases

Published Papers (5 papers)

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Research

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15 pages, 1265 KiB

Open AccessCommunication

Recombinant Antibodies against Mycolactone

by Leslie Naranjo, Fortunato Ferrara, Nicolas Blanchard, Caroline Demangel, Sara D’Angelo, M. Frank Erasmus, Andre A. Teixeira and Andrew R.M. Bradbury

Toxins 2019, 11(6), 346; https://doi.org/10.3390/toxins11060346 - 17 Jun 2019

Cited by 8 | Viewed by 4176

Abstract

In the past, it has proved challenging to generate antibodies against mycolactone, the primary lipidic toxin A of Mycobacterium ulcerans causing Buruli ulcer, due to its immunosuppressive properties. Here we show that in vitro display, comprising both phage and yeast display, can be used to select antibodies recognizing mycolactone from a large human naïve phage antibody library. Ten different antibodies were isolated, and hundreds more identified by next generation sequencing. These results indicate the value of in vitro display methods to generate antibodies against difficult antigenic targets such as toxins, which cannot be used for immunization unless inactivated by structural modification. The possibility to easily generate anti-mycolactone antibodies is an exciting prospect for the development of rapid and simple diagnostic/detection methods. Full article

(This article belongs to the Special Issue Mycolactone: Lipid-Like Immunosuppressive Toxin of Buruli Ulcer)

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15 pages, 1296 KiB

Open AccessEditor’s ChoiceArticle

Understanding the Significance of Biochemistry in the Storage, Handling, Purification, and Sampling of Amphiphilic Mycolactone

by Jessica Z. Kubicek-Sutherland, Dung M. Vu, Aaron S. Anderson, Timothy C. Sanchez, Paul J. Converse, Ricardo Martí-Arbona, Eric L. Nuermberger, Basil I. Swanson and Harshini Mukundan

Toxins 2019, 11(4), 202; https://doi.org/10.3390/toxins11040202 - 04 Apr 2019

Cited by 13 | Viewed by 4036

Abstract

Mycolactone, the amphiphilic macrolide toxin secreted by Mycobacterium ulcerans, plays a significant role in the pathology and manifestations of Buruli ulcer (BU). Consequently, it follows that the toxin is a suitable target for the development of diagnostics and therapeutics for this disease. Yet, several challenges have deterred such development. For one, the lipophilic nature of the toxin makes it difficult to handle and store and contributes to variability associated with laboratory experimentation and purification yields. In this manuscript, we have attempted to incorporate our understanding of the lipophilicity of mycolactone in order to define the optimal methods for the storage, handling, and purification of this toxin. We present a systematic correlation of variability associated with measurement techniques (thin-layer chromatography (TLC), mass spectrometry (MS), and UV-Vis spectrometry), storage conditions, choice of solvents, as well as the impact of each of these on toxin function as assessed by cellular cytotoxicity. We also compared natural mycolactone extracted from bacterial culture with synthesized toxins in laboratory (solvents, buffers) and physiologically relevant (serum) matrices. Our results point to the greater stability of mycolactone in organic, as well as detergent-containing, solvents, regardless of the container material (plastic, glass, or silanized tubes). They also highlight the presence of toxin in samples that may be undetectable by any one technique, suggesting that each detection approach captures different configurations of the molecule with varying specificity and sensitivity. Most importantly, our results demonstrate for the very first time that amphiphilic mycolactone associates with host lipoproteins in serum, and that this association will likely impact our ability to study, diagnose, and treat Buruli ulcers in patients. Full article

(This article belongs to the Special Issue Mycolactone: Lipid-Like Immunosuppressive Toxin of Buruli Ulcer)

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16 pages, 2045 KiB

Open AccessEditor’s ChoiceArticle

Molecular Docking and Dynamics Simulation Studies Predict Munc18b as a Target of Mycolactone: A Plausible Mechanism for Granule Exocytosis Impairment in Buruli Ulcer Pathogenesis

by Samuel K. Kwofie, Bismark Dankwa, Kweku S. Enninful, Courage Adobor, Emmanuel Broni, Alfred Ntiamoah and Michael D. Wilson

Toxins 2019, 11(3), 181; https://doi.org/10.3390/toxins11030181 - 25 Mar 2019

Cited by 30 | Viewed by 6203

Abstract

Ulcers due to infections with Mycobacterium ulcerans are characterized by complete lack of wound healing processes, painless, an underlying bed of host dead cells and undermined edges due to necrosis. Mycolactone, a macrolide produced by the mycobacterium, is believed to be the toxin responsible. Of interest and relevance is the knowledge that Buruli ulcer (BU) patients remember experiencing trauma previously at the site of the ulcers, suggesting an impairment of wound healing processes, the plausible effect due to the toxin. Wound healing processes involve activation of the blood platelets to release the contents of the dense granules mainly serotonin, calcium ions, and ADP/ATP by exocytosis into the bloodstream. The serotonin release results in attracting more platelets and mast cells to the wound site, with the mast cells also undergoing degranulation, releasing compounds into the bloodstream by exocytosis. Recent work has identified interference in the co-translational translocation of many secreted proteins via the endoplasmic reticulum and cell death involving Wiskott-Aldrich syndrome protein (WASP), Sec61, and angiotensin II receptors (AT2R). We hypothesized that mycolactone by being lipophilic, passively crosses cell membranes and binds to key proteins that are involved in exocytosis by platelets and mast cells, thus inhibiting the initiation of wound healing processes. Based on this, molecular docking studies were performed with mycolactone against key soluble n-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins and regulators, namely Vesicle-associated membrane protein (VAMP8), Synaptosomal-associated protein (SNAP23, syntaxin 11, Munc13-4 (its isoform Munc13-1 was used), and Munc18b; and also against known mycolactone targets (Sec61, AT2R, and WASP). Munc18b was shown to be a plausible mycolactone target after the molecular docking studies with binding affinity of −8.5 kcal/mol. Structural studies and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding energy calculations of the mycolactone and Munc18b complex was done with 100 ns molecular dynamics simulations using GROMACS. Mycolactone binds strongly to Munc18b with an average binding energy of −247.571 ± 37.471 kJ/mol, and its presence elicits changes in the structural conformation of the protein. Analysis of the binding interactions also shows that mycolactone interacts with Arg405, which is an important residue of Munc18b, whose mutation could result in impaired granule exocytosis. These findings consolidate the possibility that Munc18b could be a target of mycolactone. The implication of the interaction can be experimentally evaluated to further understand its role in granule exocytosis impairment in Buruli ulcer. Full article

(This article belongs to the Special Issue Mycolactone: Lipid-Like Immunosuppressive Toxin of Buruli Ulcer)

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14 pages, 1947 KiB

Open AccessArticle

Environmental Variations in Mycobacterium ulcerans Transcriptome: Absence of Mycolactone Expression in Suboptimal Environments

by Daniel Sanhueza, Jean-François Guégan, Heather Jordan and Christine Chevillon

Toxins 2019, 11(3), 146; https://doi.org/10.3390/toxins11030146 - 04 Mar 2019

Cited by 3 | Viewed by 3205

Abstract

Buruli ulcer is a neglected tropical infectious disease, produced by the environmentally persistent pathogen Mycobacterium ulcerans (MU). Neither the ecological niche nor the exact mode of transmission of MU are completely elucidated. However, some environmental factors, such as the concentration in chitin and pH values, were reported to promote MU growth in vitro. We pursued this research using next generation sequencing (NGS) and mRNA sequencing to investigate potential changes in MU genomic expression profiles across in vitro environmental conditions known to be suitable for MU growth. Supplementing the growth culture medium in either chitin alone, calcium alone, or in both chitin and calcium significantly impacted the MU transcriptome and thus several metabolic pathways, such as, for instance, those involved in DNA synthesis or cell wall production. By contrast, some genes carried by the virulence plasmid and necessary for the production of the mycolactone toxin were expressed neither in control nor in any modified environments. We hypothesized that these genes are only expressed in stressful conditions. Our results describe important environmental determinants playing a role in the pathogenicity of MU, helping the understanding of its complex natural life cycle and encouraging further research using genomic approaches. Full article

(This article belongs to the Special Issue Mycolactone: Lipid-Like Immunosuppressive Toxin of Buruli Ulcer)

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Review

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20 pages, 3283 KiB

Open AccessReview

Could Mycolactone Inspire New Potent Analgesics? Perspectives and Pitfalls

by Marie-Line Reynaert, Denis Dupoiron, Edouard Yeramian, Laurent Marsollier and Priscille Brodin

Toxins 2019, 11(9), 516; https://doi.org/10.3390/toxins11090516 - 04 Sep 2019

Cited by 7 | Viewed by 4383

Abstract

Pain currently represents the most common symptom for which medical attention is sought by patients. The available treatments have limited effectiveness and significant side-effects. In addition, most often, the duration of analgesia is short. Today, the handling of pain remains a major challenge. One promising alternative for the discovery of novel potent analgesics is to take inspiration from Mother Nature; in this context, the detailed investigation of the intriguing analgesia implemented in Buruli ulcer, an infectious disease caused by the bacterium Mycobacterium ulcerans and characterized by painless ulcerative lesions, seems particularly promising. More precisely, in this disease, the painless skin ulcers are caused by mycolactone, a polyketide lactone exotoxin. In fact, mycolactone exerts a wide range of effects on the host, besides being responsible for analgesia, as it has been shown notably to modulate the immune response or to provoke apoptosis. Several cellular mechanisms and different targets have been proposed to account for the analgesic effect of the toxin, such as nerve degeneration, the inhibition of inflammatory mediators and the activation of angiotensin II receptor 2. In this review, we discuss the current knowledge in the field, highlighting possible controversies. We first discuss the different pain-mimicking experimental models that were used to study the effect of mycolactone. We then detail the different variants of mycolactone that were used in such models. Overall, based on the results and the discussions, we conclude that the development of mycolactone-derived molecules can represent very promising perspectives for new analgesic drugs, which could be effective for specific pain indications. Full article

(This article belongs to the Special Issue Mycolactone: Lipid-Like Immunosuppressive Toxin of Buruli Ulcer)

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