-
PLoS Neglected Tropical Diseases Dec 2015The clinical presentation of M. ulcerans disease and the safety and effectiveness of treatment may differ in elderly compared with younger populations related to... (Observational Study)
Observational Study
BACKGROUND
The clinical presentation of M. ulcerans disease and the safety and effectiveness of treatment may differ in elderly compared with younger populations related to relative immune defficiencies, co-morbidities and drug interactions. However, elderly populations with M. ulcerans disease have not been comprehensively studied.
METHODOLOGY/PRINCIPAL FINDINGS
A retrospective analysis was performed on an observational cohort of all confirmed M. ulcerans cases managed at Barwon Health from 1/1/1998-31/12/2014. The cohort included 327 patients; 131(40.0%) ≥65 years and 196(60.0%) <65 years of age. Patients ≥65 years had a shorter median duration of symptoms prior to diagnosis (p<0.01), a higher proportion with diabetes (p<0.001) and immune suppression (p<0.001), and were more likely to have lesions that were multiple (OR 4.67, 95% CI 1.78-12.31, p<0.001) and WHO category 3 (OR 4.59, 95% CI 1.98-10.59, p<0.001). Antibiotic complications occurred in 69(24.3%) treatment episodes at an increased incidence in those aged ≥65 years (OR 5.29, 95% CI 2.81-9.98, p<0.001). There were 4(1.2%) deaths, with significantly more in the age-group ≥65 years (4 compared with 0 deaths, p = 0.01). The overall treatment success rate was 92.2%. For the age-group ≥65 years there was a reduced rate of treatment success overall (OR 0.34, 95% CI 0.14-0.80, p = <0.01) and when surgery was used alone (OR 0.21, 95% CI 0.06-0.76, p<0.01). Patients ≥65 years were more likely to have a paradoxical reaction (OR 2.06, 95% CI 1.17-3.62, p = 0.01).
CONCLUSIONS/SIGNIFICANCE
Elderly patients comprise a significant proportion of M. ulcerans disease patients in Australian populations and present with more severe and advanced disease forms. Currently recommended treatments are associated with increased toxicity and reduced effectiveness in elderly populations. Increased efforts are required to diagnose M. ulcerans earlier in elderly populations, and research is urgently required to develop more effective and less toxic treatments for this age-group.
Topics: Adult; Aged; Anti-Bacterial Agents; Australia; Buruli Ulcer; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Mycobacterium ulcerans; Retrospective Studies; Survival Analysis; Treatment Outcome
PubMed: 26630648
DOI: 10.1371/journal.pntd.0004253 -
Frontiers in Immunology 2022is the causative agent of Buruli ulcer (BU), the third most common mycobacterial infection. Virulent secretes mycolactone, a polyketide toxin. Most observations of...
is the causative agent of Buruli ulcer (BU), the third most common mycobacterial infection. Virulent secretes mycolactone, a polyketide toxin. Most observations of infection are described as an extracellular milieu in the form of a necrotic ulcer. While some evidence exists of an intracellular life cycle for during infection, the exact role that mycolactone plays in this process is poorly understood. Many previous studies have relied upon the addition of purified mycolactone to cell-culture systems to study its role in pathogenesis and host-response modulation. However, this sterile system drastically simplifies the infection model and assumes that mycolactone is the only relevant virulence factor expressed by . Here we show that the addition of purified mycolactone to macrophages during infection overcomes the bacterial activation of the mechanistic target of rapamycin (mTOR) signaling pathway that plays a substantial role in regulating different cellular processes, including autophagy and apoptosis. To further study the role of mycolactone during infection, we have developed an inducible mycolactone expression system. Utilizing the mycolactone-deficient ::Tn118 strain that contains a transposon insertion in the putative beta-ketoacyl transferase (), we have successfully restored mycolactone production by expressing in a tetracycline-inducible vector system, which overcomes growth defects associated with constitutive complementation. The inducible mycolactone-expressing bacteria resulted in the establishment of infection in a murine footpad model of BU similar to that observed during the infection with wild-type . This mycolactone inducible system will allow for further analysis of the roles and functions of mycolactone during infection.
Topics: Animals; Bacterial Toxins; Buruli Ulcer; Macrolides; Mice; Mycobacterium ulcerans
PubMed: 35401531
DOI: 10.3389/fimmu.2022.750643 -
Cellular and Molecular Life Sciences :... Jul 2014Skin ulcers are most commonly due to circulatory or metabolic disorders and are a major public health concern. In developed countries, chronic wounds affect more than 1... (Review)
Review
Skin ulcers are most commonly due to circulatory or metabolic disorders and are a major public health concern. In developed countries, chronic wounds affect more than 1 % of the population and their incidence is expected to follow those observed for diabetes and obesity. In tropical and subtropical countries, an additional issue is the occurrence of ulcers of infectious origins with diverse etiologies. While the severity of cutaneous Leishmaniasis correlates with protective immune responses, Buruli ulcers caused by Mycobacterium ulcerans develop in the absence of major inflammation. Based on these two examples, this review aims to demonstrate how studies on microorganism-provoked wounds can provide insight into the molecular mechanisms controlling skin integrity. We highlight the potential interest of a mouse model of non-inflammatory skin ulceration caused by intradermal injection of mycolactone, an original lipid toxin with ulcerative and immunosuppressive properties produced by M. ulcerans.
Topics: Animals; Humans; Immunity, Active; Leishmania; Macrolides; Mice; Mycobacterium ulcerans; Skin Ulcer
PubMed: 24445815
DOI: 10.1007/s00018-014-1561-z -
PLoS Neglected Tropical Diseases Jan 2019Zoonotic pathogens respond to changes in host range and/or pathogen, vector and host ecology. Environmental changes (biodiversity, habitat changes, variability in...
BACKGROUND
Zoonotic pathogens respond to changes in host range and/or pathogen, vector and host ecology. Environmental changes (biodiversity, habitat changes, variability in climate), even at a local level, lead to variability in environmental pathogen dynamics and can facilitate their transmission from natural reservoirs to new susceptible hosts. Whilst the environmental dynamics of aquatic bacteria are directly linked to seasonal changes of their habitat they also rely on the ecological processes underpining their transmission. However data allowing the comparison of these ecological processes are lacking. Here we compared the environmental dynamics of generalist and vector-borne aquatic bacterial pathogens in the same unit of time and space, and across rural and urban habitats in French Guiana (South America).
PRINCIPAL FINDINGS
Using Leptospira sp. and Mycobacterium ulcerans we performed an environmental survey that allowed the detection of both pathogens in urban vs. rural areas, and during rainy vs. dry weather conditions. All samples were subjected to qPCR amplifications of LipL32 (Leptospira sp.) and IS2404 and KR (M. ulcerans) genetic markers. We found (i) a greater presence of M. ulcerans in rural areas compared with Leptospira sp., (ii) that modified urban environments were more favourable to the establishment of both pathogens, (iii) that Leptospira sp. presence was enhanced during the rainy season and M. ulcerans during the dry period, and (iv) differences in the spatial distribution of both bacteria across urban sites, probably due to the mode of dissemination of each pathogen in the environment.
CONCLUSIONS
We propose that in French Guiana simplified and modified urban ecosystems might favour leptospirosis and Buruli ulcer emergence and transmission. Moreover, disease risk was also constrained by seasonality. We suggest that the prevention of aquatic bacterial disease emergence in impoverished urban areas of developing countries would benefit from seasonal diseases targeted surveys, which would maximise limited budgets from cash-strapped health agencies.
Topics: Environmental Microbiology; French Guiana; Humans; Leptospira; Mycobacterium ulcerans; Rural Population; Seasons; Spatio-Temporal Analysis; Urban Population
PubMed: 30615683
DOI: 10.1371/journal.pntd.0007074 -
Scientific Reports Jun 2021Buruli ulcer is a neglected tropical disease caused by the environmental pathogen, Mycobacterium ulcerans whose major virulence factor is mycolactone, a lipid cytotoxic...
Buruli ulcer is a neglected tropical disease caused by the environmental pathogen, Mycobacterium ulcerans whose major virulence factor is mycolactone, a lipid cytotoxic molecule. Buruli ulcer has high morbidity, particularly in rural West Africa where the disease is endemic. Data have shown that infected lesions of Buruli ulcer patients can be colonized by quorum sensing bacteria such as Staphylococcus aureus, S. epidermidis, and Pseudomonas aeruginosa, but without typical pathology associated with those pathogens' colonization. M. ulcerans pathogenesis may not only be an individual act but may also be dependent on synergistic or antagonistic mechanisms within a polymicrobial network. Furthermore, co-colonization by these pathogens may promote delayed wound healing, especially after the initiation of antibiotic therapy. Hence, it is important to understand the interaction of M. ulcerans with other bacteria encountered during skin infection. We added mycolactone to S. aureus and incubated for 3, 6 and 24 h. At each timepoint, S. aureus growth and hemolytic activity was measured, and RNA was isolated to measure virulence gene expression through qPCR and RNASeq analyses. Results showed that mycolactone reduced S. aureus hemolytic activity, suppressed hla promoter activity, and attenuated virulence genes, but did not affect S. aureus growth. RNASeq data showed mycolactone greatly impacted S. aureus metabolism. These data are relevant and significant as mycolactone and S. aureus sensing and response at the transcriptional, translational and regulation levels will provide insight into biological mechanisms of interspecific interactions that may play a role in regulation of responses such as effects between M. ulcerans, mycolactone, and S. aureus virulence that will be useful for treatment and prevention.
Topics: Gene Expression Regulation, Bacterial; Hemolysis; Humans; Macrolides; Microbial Interactions; Mycobacterium Infections, Nontuberculous; Mycobacterium ulcerans; Promoter Regions, Genetic; Staphylococcal Infections; Staphylococcus aureus
PubMed: 34083568
DOI: 10.1038/s41598-021-89177-5 -
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 -
Immunological Reviews May 2021Mycobacterium ulcerans causes Buruli ulcer, a neglected tropical skin disease manifesting as chronic wounds that can leave victims with major, life-long deformity and... (Review)
Review
Mycobacterium ulcerans causes Buruli ulcer, a neglected tropical skin disease manifesting as chronic wounds that can leave victims with major, life-long deformity and disability. Differently from other mycobacterial pathogens, M ulcerans produces mycolactone, a diffusible lipid factor with unique cytotoxic and immunomodulatory properties. Both traits result from mycolactone targeting Sec61, the entry point of the secretory pathway in eukaryotic cells. By inhibiting Sec61, mycolactone prevents the host cell's production of secreted proteins, and most of its transmembrane proteins. This molecular blockade dramatically alters the functions of immune cells, thereby the generation of protective immunity. Moreover, sustained inhibition of Sec61 triggers proteotoxic stress responses leading to apoptotic cell death, which can stimulate vigorous immune responses. The dynamics of bacterial production of mycolactone and elimination by infected hosts thus critically determine the balance between its immunostimulatory and immunosuppressive effects. Following an introduction summarizing the essential information on Buruli ulcer disease, this review focuses on the current state of knowledge regarding mycolactone's regulation and biodistribution. We then detail the consequences of mycolactone-mediated Sec61 blockade on initiation and maintenance of innate and adaptive immune responses. Finally, we discuss the key questions to address in order to improve immunity to M ulcerans, and how increased knowledge of mycolactone biology may pave the way to innovative therapeutics.
Topics: Buruli Ulcer; Humans; Macrolides; Mycobacterium ulcerans; Tissue Distribution
PubMed: 33607704
DOI: 10.1111/imr.12956 -
PLoS Neglected Tropical Diseases Apr 2020Buruli ulcer (BU) is a subcutaneous necrotic infection of the skin caused by Mycobacterium ulcerans. It is the third most common human mycobacterial disease after... (Meta-Analysis)
Meta-Analysis
Buruli ulcer (BU) is a subcutaneous necrotic infection of the skin caused by Mycobacterium ulcerans. It is the third most common human mycobacterial disease after tuberculosis (TB) and leprosy. The available methods for detection of the bacilli in lesions are microscopic detection, isolation and cultivation of the bacterium, histopathology, and polymerase chain reaction (PCR). These methods, although approved by the World Health Organization (WHO), have infrastructural and resource challenges in medical centres and cell-mediated immunity (CMI) and/or serology-based tests have been suggested as easier and more appropriate for accurate assessment of the disease, especially in remote or underdeveloped areas. This study systematically reviewed and conducted a meta-analysis for all research aimed at developing cell-mediated immunity (CMI) and/or serology-based tests for M. ulcerans disease. Information for this review was searched through PubMed and Web of Science databases and identified up to June 2019. References from relevant articles and reports from the WHO Annual Meeting of the Global Buruli Ulcer Initiative were also used. Twelve studies beginning in 1952, that attempted to develop CMI and/or serology-based tests for the disease were identified. These studies addressed issues of specificity and sensitivity in context of antigen composition as well as study heterogeneity and bias. The two main types of antigenic preparations considered were pathogen-derived and recombinant protein preparations. There was slight difference in test performance when M. ulcerans recombinant proteins [positivity: 67.5%; 32.5%] or pathogen-derived [positivity: 76.0%; 24.0%] preparations were used as test antigens among BU patients. However, pathogen-derived preparations were better at differentiating between patients and control groups [odds ratio (OR) of 27.92, 95%CI: 5.05-154.28]. This was followed by tests with the recombinant proteins [OR = 1.23, 95%CI: 0.27-5.62]. Overall, study heterogeneity index, I2 was 92.4% (p = 0.000). It is apparent from this review that standardisation is needed in any future CMI and/or serology-based tests used for M. ulcerans disease.
Topics: Buruli Ulcer; Databases, Factual; Humans; Immunity, Cellular; Leprosy; Mycobacterium ulcerans; Polymerase Chain Reaction; Serologic Tests
PubMed: 32251470
DOI: 10.1371/journal.pntd.0008172 -
The Pan African Medical Journal Aug 2013Buruli ulcer (BU) is a cutaneous neglected tropical disease caused by Mycobacterium ulcerans. Synthesizing the evidence on their efficacy of antibiotic in the management... (Review)
Review
Buruli ulcer (BU) is a cutaneous neglected tropical disease caused by Mycobacterium ulcerans. Synthesizing the evidence on their efficacy of antibiotic in the management of BU can help to better define their roles, identify weaknesses and inform clinicians on relevant measures than can be used to control BU. Our objectives is to assess the clinical efficacy of Rifampicin-Streptomycin given for 8 weeks of treatment of early M. ulcerans infection. We searched the following electronic databases from January 2005 to July 2012: Medline, EMBASE (Excerpta Medica Database), The Cochrane Library, Google Scholar, CINAHL (Cumulative Index to Nursing and Allied Health Literature), WHOLIS (World Health Organization Library Database), LILACS (Latin American and Caribbean Literature on Health Sciences) and contacted experts in the field. There were no restrictions to language or publication status. All study designs that could provide the information we sought for were eligible provided the studies were conducted in the third world. Critical appraisal of all identified citations was done independently by three authors to establish the possible relevance of the articles for inclusion in the review. Of the 115 studies, 09 papers met the inclusion criteria. The duration of treatment ranged from 8 to 48 weeks depending on the severity. Oral chemotherapy alone obtained a curative rate of 50%. The "dual" mode of treatment (surgery + chemotherapy) reduced hospital admission period from 90 to 39.8 days, that's to 44.2%. This treatment for early stages could therefore replace surgery and in severe cases, is an indispensable aid before surgery. These results confirmed that the daily administration of Rifampicin and Streptomycin is an effective treatment for M. ulcerans infection in an early stage. Subsequent systematic reviews should be conducted to determine if antibiotics could heal injuries without resorting to surgery and to compare different treatment durations.
Topics: Administration, Oral; Drug Therapy, Combination; Hospitalization; Humans; Mycobacterium Infections, Nontuberculous; Mycobacterium ulcerans; Rifampin; Streptomycin; Surgical Procedures, Operative; Treatment Outcome
PubMed: 24396561
DOI: 10.11604/pamj.2013.15.155.2341 -
International Journal of Infectious... Aug 2010Mycobacterium ulcerans infection (Buruli ulcer) causes necrotizing lesions that may lead to scarring, contractures, osteomyelitis, and even amputation. Despite decades... (Review)
Review
Mycobacterium ulcerans infection (Buruli ulcer) causes necrotizing lesions that may lead to scarring, contractures, osteomyelitis, and even amputation. Despite decades of research, the reservoirs and modes of transmission for M. ulcerans remain obscure. A thorough evaluation of the potential risk factors examined in comparative epidemiological studies may help to identify likely transmission routes. A systematic search of the literature found that poor wound care, failure to wear protective clothing, and living or working near water bodies were commonly identified risk factors. Socioeconomic status, BCG vaccination, and direct water contact were not associated with significantly increased or decreased risk of infection. Additional comparative studies are required to clarify the potential roles of water contact and insect bites in transmitting M. ulcerans to humans.
Topics: Adolescent; Animals; Buruli Ulcer; Case-Control Studies; Child; Child, Preschool; Female; Humans; Insect Bites and Stings; Male; Mycobacterium ulcerans; Risk Factors
PubMed: 20185351
DOI: 10.1016/j.ijid.2009.11.013