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Infection and Immunity Jan 2011Buruli ulcer is a neglected infectious disease caused by Mycobacterium ulcerans and is characterized by necrotic cutaneous lesions induced by the exotoxin mycolactone....
Buruli ulcer is a neglected infectious disease caused by Mycobacterium ulcerans and is characterized by necrotic cutaneous lesions induced by the exotoxin mycolactone. Despite evidence of Th1-mediated protective immunity, M. ulcerans infection has been associated with systemic immunosuppression. We show that early during mouse infection with either mycolactone-positive or negative strains, pathogen-specific gamma interferon (IFN-γ)-producing T cells developed in the draining lymph node (DLN). CD4(+) cells migrated to the infection foci, but progressive infection with virulent M. ulcerans led to the local depletion of recruited cells. Moreover, dissemination of virulent M. ulcerans to the DLN was accompanied by extensive DLN apoptotic cytopathology, leading to depletion of CD4(+) T cells and abrogation of IFN-γ expression. Advanced footpad infection with virulent M. ulcerans did not induce increased susceptibility to systemic coinfection by Listeria monocytogenes. These results show that infection with M. ulcerans efficiently triggers a mycobacterium-specific T-cell response in the DLN and that progression of infection with highly virulent M. ulcerans leads to a local and regional suppression of that immune response, but without induction of systemic immunosuppression. These results suggest that prophylactic and/or therapeutic interventions to prevent dissemination of M. ulcerans to DLN during the early phase of infection would contribute for the maintenance of protective immunity and disease control.
Topics: Animals; Apoptosis; Bacterial Toxins; Buruli Ulcer; DNA-Binding Proteins; Female; Immune Tolerance; Macrolides; Mice; Mice, Nude; Mycobacterium ulcerans; T-Lymphocytes; Time Factors; Virulence
PubMed: 20974825
DOI: 10.1128/IAI.00820-10 -
PLoS Neglected Tropical Diseases Feb 2019Access to an accurate diagnostic test for Buruli ulcer (BU) is a research priority according to the World Health Organization. Nucleic acid amplification of insertion...
BACKGROUND
Access to an accurate diagnostic test for Buruli ulcer (BU) is a research priority according to the World Health Organization. Nucleic acid amplification of insertion sequence IS2404 by polymerase chain reaction (PCR) is the most sensitive and specific method to detect Mycobacterium ulcerans (M. ulcerans), the causative agent of BU. However, PCR is not always available in endemic communities in Africa due to its cost and technological sophistication. Isothermal DNA amplification systems such as the recombinase polymerase amplification (RPA) have emerged as a molecular diagnostic tool with similar accuracy to PCR but having the advantage of amplifying a template DNA at a constant lower temperature in a shorter time. The aim of this study was to develop RPA for the detection of M. ulcerans and evaluate its use in Buruli ulcer disease.
METHODOLOGY AND PRINCIPAL FINDINGS
A specific fragment of IS2404 of M. ulcerans was amplified within 15 minutes at a constant 42°C using RPA method. The detection limit was 45 copies of IS2404 molecular DNA standard per reaction. The assay was highly specific as all 7 strains of M. ulcerans tested were detected, and no cross reactivity was observed to other mycobacteria or clinically relevant bacteria species. The clinical performance of the M. ulcerans (Mu-RPA) assay was evaluated using DNA extracted from fine needle aspirates or swabs taken from 67 patients in whom BU was suspected and 12 patients with clinically confirmed non-BU lesions. All results were compared to a highly sensitive real-time PCR. The clinical specificity of the Mu-RPA assay was 100% (95% CI, 84-100), whiles the sensitivity was 88% (95% CI, 77-95).
CONCLUSION
The Mu-RPA assay represents an alternative to PCR, especially in areas with limited infrastructure.
Topics: DNA, Bacterial; Mycobacterium ulcerans; Nucleic Acid Amplification Techniques; Reproducibility of Results; Sensitivity and Specificity
PubMed: 30707706
DOI: 10.1371/journal.pntd.0007155 -
Virulence Dec 2021is the causal agent of Buruli ulcer, a chronic infectious disease and the third most common mycobacterial disease worldwide. Without early treatment, provokes massive...
is the causal agent of Buruli ulcer, a chronic infectious disease and the third most common mycobacterial disease worldwide. Without early treatment, provokes massive skin ulcers, caused by the mycolactone toxin, its main virulence factor. However, spontaneous healing may occur in Buruli ulcer patients several months or years after the disease onset. We have shown, in an original mouse model, that bacterial load remains high and viable in spontaneously healed tissues, with a switch of to low levels of mycolactone production, adapting its strategy to survive in such a hostile environment. This original model offers the possibility to investigate the regulation of mycolactone production, by using an RNA-seq strategy to study bacterial adaptation during mouse infection. Pathway analysis and characterization of the tissue environment showed that the bacillus adapted to its new environment by modifying its metabolic activity and switching nutrient sources. Thus, ensures its survival in healing tissues by reducing its secondary metabolism, leading to an inhibition of mycolactone synthesis. These findings shed new light on mycolactone regulation and pave the way for new therapeutic strategies.
Topics: Adaptation, Biological; Animals; Buruli Ulcer; Gene Expression Regulation, Bacterial; Humans; Macrolides; Mice; Mycobacterium Infections; Mycobacterium ulcerans
PubMed: 34107844
DOI: 10.1080/21505594.2021.1929749 -
Emerging Infectious Diseases Dec 2017To identify potential reservoirs/vectors of Mycobacterium ulcerans in northern Queensland, Australia, we analyzed environmental samples collected from the Daintree River...
To identify potential reservoirs/vectors of Mycobacterium ulcerans in northern Queensland, Australia, we analyzed environmental samples collected from the Daintree River catchment area, to which Buruli ulcer is endemic, and adjacent coastal lowlands by species-specific PCR. We detected M. ulcerans DNA in soil, mosquitoes, and excreta of bandicoots, which are small terrestrial marsupials.
Topics: Animals; Buruli Ulcer; Culicidae; DNA, Bacterial; Endemic Diseases; Feces; Humans; Insect Vectors; Marsupialia; Mycobacterium ulcerans; Polymerase Chain Reaction; Queensland; Soil Microbiology
PubMed: 29148373
DOI: 10.3201/eid2312.170780 -
PLoS Neglected Tropical Diseases Jul 2021Nontuberculosis mycobacterial (NTM) infections are increasing in prevalence across the world. In many cases, treatment options for these infections are limited. However,...
Nontuberculosis mycobacterial (NTM) infections are increasing in prevalence across the world. In many cases, treatment options for these infections are limited. However, there has been progress in recent years in the development of new antimycobacterial drugs. Here, we investigate the in vitro activity of SPR719, a novel aminobenzimidazole antibiotic and the active form of the clinical-stage compound, SPR720, against several isolates of Mycobacterium ulcerans, Mycobacterium marinum and Mycobacterium chimaera. We show that SPR719 is active against these NTM species with a MIC range of 0.125-4 μg/ml and that this compares favorably with the commonly utilized antimycobacterial antibiotics, rifampicin and clarithromycin. Our findings suggest that SPR720 should be further evaluated for the treatment of NTM infections.
Topics: Anti-Bacterial Agents; DNA Gyrase; Drug Resistance, Bacterial; Gene Expression Regulation, Bacterial; Mutation; Mycobacterium; Mycobacterium marinum; Mycobacterium ulcerans
PubMed: 34310615
DOI: 10.1371/journal.pntd.0009636 -
PLoS Neglected Tropical Diseases Mar 2014Buruli ulcer (BU), a neglected tropical disease of the skin and subcutaneous tissue, is caused by Mycobacterium ulcerans and is the third most common mycobacterial...
Buruli ulcer (BU), a neglected tropical disease of the skin and subcutaneous tissue, is caused by Mycobacterium ulcerans and is the third most common mycobacterial disease after tuberculosis and leprosy. While there is a strong association of the occurrence of the disease with stagnant or slow flowing water bodies, the exact mode of transmission of BU is not clear. M. ulcerans has emerged from the environmental fish pathogen M. marinum by acquisition of a virulence plasmid encoding the enzymes required for the production of the cytotoxic macrolide toxin mycolactone, which is a key factor in the pathogenesis of BU. Comparative genomic studies have further shown extensive pseudogene formation and downsizing of the M. ulcerans genome, indicative for an adaptation to a more stable ecological niche. This has raised the question whether this pathogen is still present in water-associated environmental reservoirs. Here we show persistence of M. ulcerans specific DNA sequences over a period of more than two years at a water contact location of BU patients in an endemic village of Cameroon. At defined positions in a shallow water hole used by the villagers for washing and bathing, detritus remained consistently positive for M. ulcerans DNA. The observed mean real-time PCR Ct difference of 1.45 between the insertion sequences IS2606 and IS2404 indicated that lineage 3 M. ulcerans, which cause human disease, persisted in this environment after successful treatment of all local patients. Underwater decaying organic matter may therefore represent a reservoir of M. ulcerans for direct infection of skin lesions or vector-associated transmission.
Topics: Adult; Buruli Ulcer; Cameroon; Child; Child, Preschool; Cluster Analysis; DNA Transposable Elements; DNA, Bacterial; Endemic Diseases; Female; Genotype; Humans; Male; Middle Aged; Molecular Epidemiology; Mycobacterium ulcerans; Real-Time Polymerase Chain Reaction; Rural Population; Water Microbiology
PubMed: 24675964
DOI: 10.1371/journal.pntd.0002756 -
Tropical Medicine & International... Jul 2001Mycobacterium ulcerans disease, also known as Buruli ulcer (BU), is a disease of subcutaneous fat tissue. BU is prevalent in riverine and swamp areas of the tropical... (Review)
Review
Mycobacterium ulcerans disease, also known as Buruli ulcer (BU), is a disease of subcutaneous fat tissue. BU is prevalent in riverine and swamp areas of the tropical zone in Africa, Asia and South America, and a few scattered foci in Australia. The mode of transmission of M. ulcerans has not been fully elucidated, but inoculation into the subcutaneous tissues probably occurs through penetrating skin trauma. BU has not been linked with HIV infection. Antimycobacterial drug treatment is ineffective, and treatment is surgical. Patients eventually develop scars and contractures, with resulting disabilities, and the disease imposes a large burden on affected populations. The incidence of BU has dramatically increased in West African countries over the last decade. There is an urgent need for research into host and environmental risk factors for BU in order to develop effective strategies to combat this disease. We review possible genetic host susceptibility factors for BU that are relevant in other mycobacterial diseases: natural resistance-associated macrophage protein-1 (NRAMP-1), HLA-DR, vitamin D3 receptor, mannose binding protein, interferon-gamma (IFN-gamma) receptor, tumour necrosis factor alpha (TNF-alpha), interleukin (IL)-1 alpha, 1 beta and their receptor antagonists; and IL-12. Schistosoma haematobium infection is highly endemic in many BU foci in West Africa, with a striking increase in transmission after river dams were constructed. This observation, and the observations from interaction of schistosomiasis and tuberculosis, have fueled our hypothesis that schistosomiasis is a risk factor for BU by driving the host immune response towards a predominantly Th-2 pattern, away from a Th-1 preponderant protection against mycobacterial infection. If the latter hypothesis is confirmed, enhanced schistosomiasis control should impact on BU.
Topics: Carrier Proteins; Cation Transport Proteins; Disease Susceptibility; Humans; Membrane Proteins; Mycobacterium Infections, Nontuberculous; Mycobacterium ulcerans; Polymorphism, Genetic; Risk Factors; Schistosomiasis
PubMed: 11469950
DOI: 10.1046/j.1365-3156.2001.00746.x -
PLoS Neglected Tropical Diseases May 2024Critical scientific questions remain regarding infection with Mycobacterium ulcerans, the organism responsible for the neglected tropical disease, Buruli ulcer (BU). A...
Critical scientific questions remain regarding infection with Mycobacterium ulcerans, the organism responsible for the neglected tropical disease, Buruli ulcer (BU). A controlled human infection model has the potential to accelerate our knowledge of the immunological correlates of disease, to test prophylactic interventions and novel therapeutics. Here we present microbiological evidence supporting M. ulcerans JKD8049 as a suitable human challenge strain. This non-genetically modified Australian isolate is susceptible to clinically relevant antibiotics, can be cultured in animal-free and surfactant-free media, can be enumerated for precise dosing, and has stable viability following cryopreservation. Infectious challenge of humans with JKD8049 is anticipated to imitate natural infection, as M. ulcerans JKD8049 is genetically stable following in vitro passage and produces the key virulence factor, mycolactone. Also reported are considerations for the manufacture, storage, and administration of M. ulcerans JKD8049 for controlled human infection.
Topics: Mycobacterium ulcerans; Buruli Ulcer; Humans; Anti-Bacterial Agents; Australia
PubMed: 38701090
DOI: 10.1371/journal.pntd.0011979 -
International Journal of... 2021Buruli ulcer (BU) is a neglected tropical disease caused by the Mycobacterium ulcerans. BU is an endemic disease in many communities in sub-Saharan Africa where...
BACKGROUND
Buruli ulcer (BU) is a neglected tropical disease caused by the Mycobacterium ulcerans. BU is an endemic disease in many communities in sub-Saharan Africa where population have long history of using medicinal plants for treatment. Indeed, several medicinal plants have been documented against BU and related conditions. The present study was undertaken to prove the efficacy of seven medicinal plants documented for the treatment of mycobacterial infections and related symptoms in Ghana.
METHOD
Antimycobacterial activity of the stem bark extracts and reference control drugs were conducted using the resazurin microtiter assay (REMA) assay method in clear round bottom 96-well microtiter plates. The extracts that showed anti-mycobacterium ulcerans activity were assessed for cytotoxicity using the Alamar blue assay.
RESULTS
Overall, The Cryptolepis sanguinolenta root aqueous extract exhibited the highest antimycobacterial activity (MIC=64 μg/mL) followed by Cleistopholis patens (MIC=256 μg/mL). Based on the marked activity of the Cryptolepis sanguinolenta extracts, pure cryptolepine, its major metabolite recorded a MIC value of 32 μg/mL. These extracts with considerable antimycobacterial activity showed 50% cytotoxic concentration (CC50) ranging from 94 to 384 μg/mL.
CONCLUSIONS
Thus, Cleistopholis patens and Cryptolepis sanguinolenta are primed for further studies and could afford novel drugs for the mitigation of buruli ulcer disease.
Topics: Alkaloids; Buruli Ulcer; Humans; Mycobacterium ulcerans; Plant Extracts; Plants, Medicinal
PubMed: 33707373
DOI: 10.4103/ijmy.ijmy_243_20 -
Expert Opinion on Biological Therapy Feb 2009Buruli ulcer is a necrotizing skin disease caused by Mycobacterium ulcerans. Major necrosis with abundant clusters of extracellularly replicating mycobacteria and only... (Review)
Review
Buruli ulcer is a necrotizing skin disease caused by Mycobacterium ulcerans. Major necrosis with abundant clusters of extracellularly replicating mycobacteria and only minor leukocyte infiltration are characteristic histopathologic features of the disease. Mycolactone, a cytotoxic macrolide exotoxin of M. ulcerans, plays a key role in the development of this pathology. Antimicrobial therapy, such as rifampicin/streptomycin that was recently introduced, seems to lead to phagocytosis of mycobacteria and massive leukocyte infiltration, which culminates in the development of ectopic lymphoid structures in the lesions. Whereas the curative effect of the antibiotic treatment may be supported by immune defense mechanisms, persisting mycobacterial antigens and immunostimulators occasionally also seem to cause apparent reactivation of the disease. This seems to be related to excessive immunostimulation rather than to incomplete killing of the pathogen.
Topics: Animals; Antitubercular Agents; Buruli Ulcer; Disease Models, Animal; Humans; Mycobacterium ulcerans; Virulence
PubMed: 19236249
DOI: 10.1517/14712590802631854