scholarly journals Recent advances: role of mycolactone in the pathogenesis and monitoring of Mycobacterium ulcerans infection/Buruli ulcer disease

2015 ◽  
Vol 18 (1) ◽  
pp. 17-29 ◽  
Author(s):  
Fred Stephen Sarfo ◽  
Richard Phillips ◽  
Mark Wansbrough‐Jones ◽  
Rachel E. Simmonds
Keyword(s):  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Ulcer Disease ◽  
Recent Advances

scholarly journals Mechanism of Mycolactone Toxin Membrane Permeation: Atomistic vs Coarse-Grained MARTINI Simulations

2018 ◽  
Author(s):  
F. Aydin ◽  
R. Sun ◽  
J. M. J. Swanson
Keyword(s):  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Coarse Grained ◽  
Membrane Permeation ◽  
Lipid Trafficking ◽  
Ulcer Disease ◽  
Cellular Processes ◽  
Coarse Grained Simulations ◽  
Dynamics Simulations

ABSTRACTMycolactone, a cytotoxic and immunosuppressive macrolide produced by Mycobacterium ulcerans, is the central virulent factor in the skin disease Buruli ulcer. This multifunctional cytotoxin affects fundamental cellular processes such as cell adhesion, immune response and cell death by targeting various cellular structures. Developing effective diagnostics that target mycolactone has been challenging, potentially due to suspected interactions with lipophilic architectures, including membranes. To better understand the pathogenesis of Buruli ulcer disease, aid in the development of diagnostics, and learn how amphiphiles in general use lipid trafficking to navigate the host environment, we seek to understand the nature of mycolactone-membrane interactions. Herein we characterize how the two dominant isomers of mycolactone (A and B) interact with and permeate DPPC membranes with all-atom molecular dynamics simulations employing transition tempered metadynamics, and compare these results with those obtained by MARTINI coarse-grained simulations. Our all-atom simulations reveal that both isomers have a strong preference to associate with the membrane, although their mechanisms and energetics of membrane permeation differ slightly. Water molecules are found to play an important role in the permeation process. Although the MARTINI coarse-grained simulations give the correct free energy of membrane association, they fail to capture the mechanism of permeation and role of water during permeation as seen in all-atom simulations.

scholarly journals Molecular Mechanisms Underpinning the Circulation and Cellular Uptake of Mycobacterium ulcerans Toxin Mycolactone

2021 ◽  
Vol 12 ◽  
Author(s):  
Bruno Tello Rubio ◽  
Florence Bugault ◽  
Blandine Baudon ◽  
Bertrand Raynal ◽  
Sébastien Brûlé ◽  
...  
Keyword(s):  
Cellular Uptake ◽  
Molecular Mechanisms ◽  
Scavenger Receptor ◽  
Buruli Ulcer ◽  
Systemic Circulation ◽  
Mycobacterium Ulcerans ◽  
Host Cells ◽  
Ulcer Disease ◽  
Major Mechanism ◽  
Specific Association

Mycolactone is a diffusible lipid toxin produced by Mycobacterium ulcerans, the causative agent of Buruli ulcer disease. Altough bacterially derived mycolactone has been shown to traffic from cutaneous foci of infection to the bloodstream, the mechanisms underpinning its access to systemic circulation and import by host cells remain largely unknown. Using biophysical and cell-based approaches, we demonstrate that mycolactone specific association to serum albumin and lipoproteins is necessary for its solubilization and is a major mechanism to regulate its bioavailability. We also demonstrate that Scavenger Receptor (SR)-B1 contributes to the cellular uptake of mycolactone. Overall, we suggest a new mechanism of transport and cell entry, challenging the dogma that the toxin enters host cells via passive diffusion.

scholarly journals Aquatic Snails, Passive Hosts of Mycobacterium ulcerans

2004 ◽  
Vol 70 (10) ◽  
pp. 6296-6298 ◽  
Author(s):  
Laurent Marsollier ◽  
Tchibozo Sévérin ◽  
Jacques Aubry ◽  
Richard W. Merritt ◽  
Jean-Paul Saint André ◽  
...  
Keyword(s):  
Buruli Ulcer ◽  
Indirect Evidence ◽  
Mycobacterium Ulcerans ◽  
Aquatic Environments ◽  
Potential Vector ◽  
Ulcer Disease ◽  
Skin Ulcers ◽  
Chronic Skin ◽  
Favorable Conditions ◽  
Water Bugs

ABSTRACT Accumulative indirect evidence of the epidemiology of Mycobacterium ulcerans infections causing chronic skin ulcers (i.e., Buruli ulcer disease) suggests that the development of this pathogen and its transmission to humans are related predominantly to aquatic environments. We report that snails could transitorily harbor M. ulcerans without offering favorable conditions for its growth and replication. A novel intermediate link in the transmission chain of M. ulcerans becomes likely with predator aquatic insects in addition to phytophage insects. Water bugs, such as Naucoris cimicoides, a potential vector of M. ulcerans, were shown to be infected specifically by this bacterium after feeding on snails experimentally exposed to M. ulcerans.

Associations Between Mycobacterium ulcerans and Aquatic Plant Communities of West Africa: Implications for Buruli Ulcer Disease

EcoHealth ◽  
2014 ◽  
Vol 11 (2) ◽  
pp. 184-196 ◽  
Author(s):  
Mollie McIntosh ◽  
Heather Williamson ◽  
M. Eric Benbow ◽  
Ryan Kimbirauskas ◽  
Charles Quaye ◽  
...  
Keyword(s):  
West Africa ◽  
Plant Communities ◽  
Aquatic Plant ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Ulcer Disease

scholarly journals Molecular characterization of Mycobacterium ulcerans DNA gyrase and identification of mutations reduced susceptibility against quinolones in vitro

2021 ◽  
Author(s):  
Hyun Kim ◽  
Shigtarou Mori ◽  
Tsuyoshi Kenri ◽  
Yasuhiko Suzuki
Keyword(s):  
Buruli Ulcer ◽  
Dna Gyrase ◽  
Resistance Mechanisms ◽  
Docking Studies ◽  
Mycobacterium Ulcerans ◽  
Amino Acid Residues ◽  
Wild Type Enzyme ◽  
Ulcer Disease

ABSTRACTBuruli ulcer disease is a neglected necrotizing and disabling cutaneous tropical illness caused by Mycobacterium ulcerans (Mul). Fluoroquinolone (FQ), used in the treatment of this disease, has been known to act by inhibiting the enzymatic activities of DNA gyrase; however, the detailed molecular basis of these characteristics and the FQ resistance mechanisms in Mul remains unknown. This study investigated the detailed molecular mechanism of Mul DNA gyrase and the contribution of FQ resistance in vitro using recombinant proteins from the Mul subsp. shinshuense and Agy99 strains with reduced sensitivity to FQs. The IC50 of FQs against Ala91Vla and Asp95Gly mutants of Mul shinshuense and Agy99 GyrA subunits were 3.7- to 42.0-fold higher than those against wild-type enzyme. Similarly, the CC25 was 10- to 210-fold higher than those for the WT enzyme. Furthermore, the interaction between the amino acid residues of WT/mutant Mul DNA gyrase and FQ side chains was assessed via molecular docking studies. This is the first detailed study showing the contribution of Mul DNA GyrA subunit mutations to reduce the susceptibility against FQs.

scholarly journals Mycolactone toxin induces an inflammatory response by targeting the IL-1β pathway: Mechanistic insight into Buruli ulcer pathophysiology

2020 ◽  
Vol 16 (12) ◽  
pp. e1009107
Author(s):  
M. Foulon ◽  
M. Robbe-Saule ◽  
J. Manry ◽  
L. Esnault ◽  
Y. Boucaud ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Inflammatory Factors ◽  
Dependent Manner ◽  
Local Inflammatory Response ◽  
Mechanistic Insight ◽  
Insight Into

Mycolactone, a lipid-like toxin, is the major virulence factor of Mycobacterium ulcerans, the etiological agent of Buruli ulcer. Its involvement in lesion development has been widely described in early stages of the disease, through its cytotoxic and immunosuppressive activities, but less is known about later stages. Here, we revisit the role of mycolactone in disease outcome and provide the first demonstration of the pro-inflammatory potential of this toxin. We found that the mycolactone-containing mycobacterial extracellular vesicles produced by M. ulcerans induced the production of IL-1β, a potent pro-inflammatory cytokine, in a TLR2-dependent manner, targeting NLRP3/1 inflammasomes. We show our data to be relevant in a physiological context. The in vivo injection of these mycolactone-containing vesicles induced a strong local inflammatory response and tissue damage, which were prevented by corticosteroids. Finally, several soluble pro-inflammatory factors, including IL-1β, were detected in infected tissues from mice and Buruli ulcer patients. Our results revisit Buruli ulcer pathophysiology by providing new insight, thus paving the way for the development of new therapeutic strategies taking the pro-inflammatory potential of mycolactone into account.

scholarly journals Analysis of Mycobacterium ulcerans-specific T-cell cytokines for diagnosis of Buruli ulcer disease and as potential indicator for disease progression

2017 ◽  
Vol 11 (2) ◽  
pp. e0005415 ◽  
Author(s):  
Norman Nausch ◽  
Daniel Antwi-Berko ◽  
Yusif Mubarik ◽  
Kabiru Mohammed Abass ◽  
Wellington Owusu ◽  
...  
Keyword(s):  
T Cell ◽  
Disease Progression ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Ulcer Disease ◽  
Potential Indicator

scholarly journals Evaluation of Buruli Ulcer Disease Surveillance System in the Ga West Municipality, Ghana, 2011–2015

2019 ◽  
Vol 2019 ◽  
pp. 1-5 ◽  
Author(s):  
Tanko Rufai ◽  
Enoch Aninagyei ◽  
Samuel Oko Sackey ◽  
Ernest Kenu ◽  
Edwin Andrew Afari
Keyword(s):  
Surveillance System ◽  
Disease Surveillance ◽  
Neglected Tropical Diseases ◽  
Buruli Ulcer ◽  
Control Program ◽  
Mycobacterium Ulcerans ◽  
Ulcer Disease ◽  
Disease Surveillance System ◽  
Key Stakeholders ◽  
Control And Prevention

Background. Buruli ulcer (BU) is one of the most neglected tropical diseases caused by Mycobacterium ulcerans. M. ulcerans infection may manifest initially as a pre-ulcerative nodule, a plaque, or oedema which breaks down to form characteristic ulcers with undermined edges. The Ga West Municipality is an endemic area for Buruli ulcer, and we evaluated the BU surveillance system to determine whether the system is meeting its objectives and to assess its attributes. Materials and Methods. We used a checklist based on Centers for Disease Control and Prevention (CDC) updated surveillance evaluation guidelines, 2006. We reviewed records and dataset on Buruli ulcer for the period 2011–2015. The evaluation was carried out at the national, regional, district, and community levels using the Ga West Municipality of the Greater Accra Region as a study site. Interviews with key stakeholders at the various levels were done using an interview guide, and observations were done with a checklist. Data were entered and analyzed using Epi info 7. Results. A total of 594 cases of Buruli ulcer were reported from 2011 to 2015 in Ga West. The number of confirmed cases decreased from 109 in 2011 to 17 in 2015. The system was useful, fairly simple, flexible, representative, and fairly acceptable. The system was sensitive with a PVP of 45.3%. Although the data quality was good with 85% of case report forms completed, there was under-reporting (3.6%), some discrepancies of data at the district, regional, and national levels. The system was moderately stable, and timeliness of reporting was 30.7%. Conclusion. The Buruli ulcer surveillance system is meeting its set objectives, and the data generated are used to reliably describe the epidemiologic situation and evaluate the results for actions and plan future interventions. There is a need for timely submission of data. We recommend that the National Buruli Ulcer Control Program (NBUCP) provides logistical support to treatment centres.

A Landscape-based Model for Predicting Mycobacterium ulcerans Infection (Buruli Ulcer Disease) Presence in Benin, West Africa

EcoHealth ◽  
2008 ◽  
Vol 5 (1) ◽  
pp. 69-79 ◽  
Author(s):  
Tyler Wagner ◽  
M. Eric Benbow ◽  
Meghan Burns ◽  
R. Christian Johnson ◽  
Richard W. Merritt ◽  
...  
Keyword(s):  
West Africa ◽  
Buruli Ulcer ◽  
Mycobacterium Ulcerans ◽  
Ulcer Disease
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