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Emerging Infectious Diseases Oct 2023To examine protective and risk factors for Buruli ulcer (BU), we conducted a case-control study of 245 adult BU cases and 481 postcode-matched controls across BU-endemic...
To examine protective and risk factors for Buruli ulcer (BU), we conducted a case-control study of 245 adult BU cases and 481 postcode-matched controls across BU-endemic areas of Victoria, Australia. We calculated age- and sex-adjusted odds ratios for socio-environmental, host, and behavioral factors associated with BU by using conditional logistic regression. Odds of BU were >2-fold for persons with diabetes mellitus and persons working outdoors who had soil contact in BU-endemic areas (compared with indoor work) but were lower among persons who had bacillus Calmette-Guérin vaccinations. BU was associated with increasing numbers of possums and with ponds and bore water use at residences. Using insect repellent, covering arms and legs outdoors, and immediately washing wounds were protective; undertaking multiple protective behaviors was associated with the lowest odds of BU. Skin hygiene/protection behaviors and previous bacillus Calmette-Guérin vaccination might provide protection against BU in BU-endemic areas.
Topics: Adult; Humans; BCG Vaccine; Buruli Ulcer; Case-Control Studies; Risk Factors; Victoria
PubMed: 37735741
DOI: 10.3201/eid2910.230011 -
The International Journal of Lower... Sep 2023Buruli ulcer is caused by , a skin infection that occurs mostly in people living in the developing economies of Africa and is considered a neglected tropical disease by...
Buruli ulcer is caused by , a skin infection that occurs mostly in people living in the developing economies of Africa and is considered a neglected tropical disease by the World Health Organization (WHO). Left untreated, it can lead to chronic wounds and loss of limbs. This disease is one of the target diseases of the WHO, and there are very limited bibliometric studies published on this subject. Also, no similar study using the Web of Science Core Collection was found in the available literature. The aim of this study was to evaluate the bibliometric analysis of the literature on Buruli ulcers. For data visualization and analysis, the open-source visualization program Biblioshiny (version 2.0) was used. Although most publications are from Ghana, the United States, and European countries have also made significant contributions. The number of publications has increased especially since 2016. The most preferred keywords in the publications were treatment, diagnosis, and transmission routes. This is the first bibliometric analysis that examines the trend of scientific publications on Buruli ulcer that have been indexed in the Web of Science. Our findings have the potential to be used by academics to improve their research.
PubMed: 37700690
DOI: 10.1177/15347346231200559 -
The Medical Journal of Australia Dec 2023
Topics: Humans; Buruli Ulcer; BCG Vaccine; Mycobacterium ulcerans; Vaccination; Australia
PubMed: 37679050
DOI: 10.5694/mja2.52096 -
Toxins Aug 2023Mycolactone is an exotoxin produced by that causes the neglected tropical skin disease Buruli ulcer. This toxin inhibits the Sec61 translocon in the endoplasmic...
Mycolactone is an exotoxin produced by that causes the neglected tropical skin disease Buruli ulcer. This toxin inhibits the Sec61 translocon in the endoplasmic reticulum (ER), preventing the host cell from producing several secretory and transmembrane proteins, resulting in cytotoxic and immunomodulatory effects. Interestingly, only one of the two dominant isoforms of mycolactone is cytotoxic. Here, we investigate the origin of this specificity by performing extensive molecular dynamics (MD) simulations with enhanced free energy sampling to query the association trends of the two isoforms with both the Sec61 translocon, using two distinct cryo-electron microscopy (cryo-EM) models as references, and the ER membrane, which serves as a toxin reservoir prior to association. Our results suggest that mycolactone B (the cytotoxic isoform) has a stronger association with the ER membrane than mycolactone A due to more favorable interactions with membrane lipids and water molecules. This could increase the reservoir of toxin proximal to the Sec61 translocon. In one model of Sec61 inhibited by mycolactone, we find that isomer B interacts more closely with residues thought to play a key role in signal peptide recognition and, thus, are essential for subsequent protein translocation. In the other model, we find that isomer B interacts more closely with the lumenal and lateral gates of the translocon, the dynamics of which are essential for protein translocation. These interactions induce a more closed conformation, which has been suggested to block signal peptide insertion and subsequent protein translocation. Collectively, these findings suggest that isomer B's unique cytotoxicity is a consequence of both increased localization to the ER membrane and channel-locking association with the Sec61 translocon, facets that could be targeted in the development of Buruli Ulcer diagnostics and Sec61-targeted therapeutics.
Topics: Humans; Buruli Ulcer; Cryoelectron Microscopy; SEC Translocation Channels
PubMed: 37624243
DOI: 10.3390/toxins15080486 -
Journal of Medical Entomology Sep 2023Aedes notoscriptus (Skuse) is a container-inhabiting mosquito endemic to Australia that vectors arboviruses and is suspected to transmit Mycobacterium ulcerans, the...
Aedes notoscriptus (Skuse) is a container-inhabiting mosquito endemic to Australia that vectors arboviruses and is suspected to transmit Mycobacterium ulcerans, the cause of Buruli ulcer. We evaluated the effectiveness of the In2Care station, which suppresses mosquito populations via the entomopathogenic fungus, Beauveria bassiana, and the insect growth regulator pyriproxyfen, the latter of which is autodisseminated among larval habitats by contaminated mosquitoes. A field trial was conducted using 110 In2Care stations in a 50,000 m2 area and results were compared to 4 control areas that did not receive the treatment. Efficacy was evaluated by comparing egg counts and measuring larvicidal impact in surrounding breeding sites. Laboratory experiments validated the effect of B. bassiana on adult survival. Results of this field trial indicate that, 6 wk after the In2Care stations were deployed, treatment site ovitraps contained 43% fewer eggs than control site ovitraps, and 33% fewer eggs after 10 wk, suggesting that the In2Care station was able to reduce the egg density of Ae. notoscriptus. Population reduction remained evident for up to 3 wk after In2Care stations were removed. Treatment site ovitraps had significantly fewer Ae. notoscriptus eclosing than control site ovitraps, confirming the pyriproxyfen autodissemination feature of the stations. An average reduction of 50% in adult eclosion was achieved. Exposure to B. bassiana resulted in four-times higher mortality among adult mosquitoes. Additionally, using fresh In2Care nettings led to an 88% decrease in average survival compared to 4-wk-old nettings. The use of In2Care stations has potential for suppressing Ae. notoscriptus egg density.
Topics: Animals; Aedes; Australia; Mosquito Vectors; Mosquito Control; Environment
PubMed: 37535973
DOI: 10.1093/jme/tjad099 -
PloS One 2023Mycolactone is a cytotoxic lipid metabolite produced by Mycobacterium ulcerans, the environmental pathogen responsible for Buruli ulcer, a neglected tropical disease....
Mycolactone is a cytotoxic lipid metabolite produced by Mycobacterium ulcerans, the environmental pathogen responsible for Buruli ulcer, a neglected tropical disease. Mycobacterium ulcerans is prevalent in West Africa, particularly found in lentic environments, where mosquitoes also occur. Researchers hypothesize mosquitoes could serve as a transmission mechanism resulting in infection by M. ulcerans when mosquitoes pierce skin contaminated with M. ulcerans. The interplay between the pathogen, mycolactone, and mosquito is only just beginning to be explored. A triple-choice assay was conducted to determine the host-seeking preference of Aedes aegypti between M. ulcerans wildtype (MU, mycolactone active) and mutant (MUlac-, mycolactone inactive). Both qualitative and quantitative differences in volatile organic compounds' (VOCs) profiles of MU and MUlac- were determined by GC-MS. Additionally, we evaluated the interplay between Ae. aegypti proximity and M. ulcerans mRNA expression. The results showed that mosquito attraction was significantly greater (126.0%) to an artificial host treated with MU than MUlac-. We found that MU and MUlac produced differential profiles of VOCs associated with a wide range of biological importance from quorum sensing (QS) to human odor components. RT-qPCR assays showed that mycolactone upregulation was 24-fold greater for MU exposed to Ae. aegypti in direct proximity. Transcriptome data indicated significant induction of ten chromosomal genes of MU involved in stress responses and membrane protein, compared to MUlac- when directly having access to or in near mosquito proximity. Our study provides evidence of possible interkingdom interactions between unicellular and multicellular species that MU present on human skin is capable of interreacting with unrelated species (i.e., mosquitoes), altering its gene expression when mosquitoes are in direct contact or proximity, potentially impacting the production of its VOCs, and consequently leading to the stronger attraction of mosquitoes toward human hosts. This study elucidates interkingdom interactions between viable M. ulcerans bacteria and Ae. aegypti mosquitoes, which rarely have been explored in the past. Our finding opens new doors for future research in terms of disease ecology, prevalence, and pathogen dispersal outside of the M. ulcerans system.
Topics: Animals; Humans; Mycobacterium ulcerans; Buruli Ulcer; Macrolides; Aedes; Gene Expression
PubMed: 37535670
DOI: 10.1371/journal.pone.0289768 -
BMC Infectious Diseases Jul 2023Mycobacterium ulcerans is the causative agent of Buruli ulcer. The pathology of M. ulcerans disease has been attributed to the secretion of a potent macrolide cytotoxin...
BACKGROUND
Mycobacterium ulcerans is the causative agent of Buruli ulcer. The pathology of M. ulcerans disease has been attributed to the secretion of a potent macrolide cytotoxin known as mycolactone which plays an important role in the virulence of the disease. Mycolactone is a biomarker for the diagnosis of BU that can be detected using the fluorescent-thin layer chromatography (f-TLC) technique. The technique relies on the chemical derivatization of mycolactone A/B with 2-naphthylboronic acid (BA) which acts as a fluorogenic chemosensor. However, background interferences due to co-extracted human tissue lipids, especially with clinical samples coupled with the subjectivity of the method call for an investigation to find an alternative to BA.
METHODS
Twenty-six commercially available arylboronic acids were initially screened as alternatives to BA using the f-TLC experiment. UV-vis measurements were also conducted to determine the absorption maximum spectra of mycolactone A/B and myco-boronic acid adducts followed by an investigation of the fluorescence-enhancing ability of the boronate ester formation between mycolactone A/B and our three most promising boronic acids (BA15, BA18, and BA21). LC-MS technique was employed to confirm the adduct formation between mycolactone and boronic acids. Furthermore, a comparative study was conducted between BA18 and BA using 6 Polymerase Chain Reaction (PCR) confirmed BU patient samples.
RESULTS
Three of the boronic acids (BA15, BA18, and BA21) produced fluorescent band intensities superior to BA. Complexation studies conducted on thin layer chromatography (TLC) using 0.1 M solution of the three boronic acids and various volumes of 10 ng/µL of synthetic mycolactone ranging from 1 µL - 9 µL corresponding to 10 ng - 90 ng gave similar results with myco-BA18 adduct emerging with the most visibly intense fluorescence bands. UV-vis absorption maxima (λ) for the free mycolactone A/B was observed at 362 nm, and the values for the adducts myco-BA15, myco-BA18, and myco-BA21 were at 272 nm, 270 nm, and 286 nm respectively. The comparable experimental λ of 362 nm for mycolactone A/B to the calculated Woodward-Fieser value of 367 nm for the fatty acid side chain of mycolactone A/B demonstrate that even though 2 cyclic boronates were formed, only the boronate of the southern side chain with the chromophore was excited by irradiation at 365 nm. Fluorescence experiments have demonstrated that coupling BA18 to mycolactone A/B along the 1,3-diols remarkably enhanced the fluorescence intensity at 537 nm. High-Resolution Mass Spectrometer (HR-MS) was used to confirm the formation of the myco-BA15 adduct. Finally, f-TLC analysis of patient samples with BA18 gave improved BA18-adduct intensities compared to the original BA-adduct.
CONCLUSION
Twenty-six commercially available boronic acids were investigated as alternatives to BA, used in the f-TLC analysis for the diagnosis of BU. Three (3) of them BA15, BA18, and BA21 gave superior fluorescence band intensity profiles. They gave profiles that were easier to interpret after the myco-boronic acid adduct formation and in experiments with clinical samples from patients with BA18 the best. BA18, therefore, has been identified as a potential alternative to BA and could provide a solution to the challenge of background interference of co-extracted human tissue lipids from clinical samples currently associated with the use of BA.
Topics: Humans; Buruli Ulcer; Chromatography, Thin Layer; Boronic Acids; Bacterial Toxins; Macrolides; Mycobacterium ulcerans; Lipids
PubMed: 37501134
DOI: 10.1186/s12879-023-08426-2 -
Emergency Medicine Australasia : EMA Aug 2023Mycobacterium ulcerans (MU) is known to be endemic in heavily touristed coastal regions of Victoria and is the cause of Buruli ulcer (BU) disease. The incidence,...
Mycobacterium ulcerans (MU) is known to be endemic in heavily touristed coastal regions of Victoria and is the cause of Buruli ulcer (BU) disease. The incidence, severity and geographic spread of MU infection/BU disease is increasing, including metropolitan Victorian suburbs. While the specifics of disease transmission and effective prevention strategies remain uncertain, severe complications can be mitigated by health systems that provide vigilant population surveillance to underpin early recognition, early specialist involvement and definitive treatment for the individual. Current theories regarding disease transmission and 'best practice' (or best guess) prevention and mitigation measures are presented herein. Opportunities to improve the health system response to this emerging public health threat are identified. It is incumbent upon all healthcare providers, including ED clinicians, to contribute by familiarising themselves with the established and emerging areas of endemicity of MU infection and the array of BU clinical presentations.
Topics: Humans; Buruli Ulcer; Victoria; Public Health; Mycobacterium ulcerans; Incidence
PubMed: 37454363
DOI: 10.1111/1742-6723.14235 -
PLoS Pathogens Jul 2023Buruli ulcer is a chronic infectious disease caused by Mycobacterium ulcerans. The pathogen persistence in host skin is associated with the development of ulcerative and...
Buruli ulcer is a chronic infectious disease caused by Mycobacterium ulcerans. The pathogen persistence in host skin is associated with the development of ulcerative and necrotic lesions leading to permanent disabilities in most patients. However, few of diagnosed cases are thought to resolve through an unknown self-healing process. Using in vitro and in vivo mouse models and M. ulcerans purified vesicles and mycolactone, we showed that the development of an innate immune tolerance was only specific to macrophages from mice able to heal spontaneously. This tolerance mechanism depends on a type I interferon response and can be induced by interferon beta. A type I interferon signature was further detected during in vivo infection in mice as well as in skin samples from patients under antibiotics regiment. Our results indicate that type I interferon-related genes expressed in macrophages may promote tolerance and healing during infection with skin damaging pathogen.
Topics: Mice; Animals; Mycobacterium ulcerans; Interferon Type I; Buruli Ulcer; Macrophages; Macrolides; Immune Tolerance
PubMed: 37428812
DOI: 10.1371/journal.ppat.1011479 -
PLoS Neglected Tropical Diseases Jun 2023Critical knowledge gaps regarding infection with Mycobacterium ulcerans, the cause of Buruli ulcer (BU), have impeded development of new therapeutic approaches and... (Review)
Review
Critical knowledge gaps regarding infection with Mycobacterium ulcerans, the cause of Buruli ulcer (BU), have impeded development of new therapeutic approaches and vaccines for prevention of this neglected tropical disease. Here, we review the current understanding of host-pathogen interactions and correlates of immune protection to explore the case for establishing a controlled human infection model of M. ulcerans infection. We also summarise the overarching safety considerations and present a rationale for selecting a suitable challenge strain.
Topics: Humans; Mycobacterium ulcerans; Buruli Ulcer; Host-Pathogen Interactions; Knowledge; Neglected Diseases
PubMed: 37384606
DOI: 10.1371/journal.pntd.0011394