What is Buruli ulcer?

Buruli ulcer is a bacterial infection of the skin that can cause serious swelling, lesions, and permanent deformity. Much of the epidemiology, transmission, and control of the disease remain unknown.

Global Burden

Buruli ulcer

Much of the epidemiology, transmission, and control of Buruli ulcer remain unknown.1,2 The disease is endemic to humid, often rural tropical climates, and has been reported in 33 countries.3 Incidence of Buruli ulcer is highest in Africa (especially Benin, Cote d’Ivoire and Ghana), though cases also occur in Latin America, Oceania and Asia.4 While the transmission of the disease is not well understood, cases are often localized to very specific districts within a region, and prevalence may vary widely within countries.2,5

Causative Agent

Buruli ulcer is caused by infection with the bacterium Mycobacterium ulcerans. The bacterium releases a toxin called mycolactone which breaks down skin and bone tissue.6 Transmission of the disease is not well understood but seems to be related to contaminated water sources in wetland areas. M. ulcerans DNA has been found inside the salivary glands of aquatic insects, which leads some researchers to believe that insect bite is the mode of transmission.5 Other scientists hypothesize that infection is caused by direct contact with infected water or aerosols, but conclusive evidence is lacking.5 Buruli ulcer is not considered contagious from human to human.4

Pathogenesis

Buruli ulcerThe first stage of infection is characterized by a painless subcutaneous nodule. On adults, these nodules are usually localized to the extremities, but on children they may present anywhere on the body. After a period of weeks to months, the nodule breaks into an ulcerated lesion that can spread and swell during the course of infection. This ulcer is formed by the cytotoxic effects of mycolactone, which slowly kills subcutaneous tissue, and can even destroy bone and connective tissues. In Benin, 14.9% of Buruli ulcer cases result in bone disease.4 Spontaneous healing can occur, probably due to a development of protective immunity, but scarring is extensive.5 While Buruli is rarely fatal, the deformity and disfigurement it causes can result in serious loss of quality of life.

Current Control Strategy

Because the mode of transmission of Buruli remains unclear, control strategies are difficult to define. Avoidance of wetlands and stagnant water sources is not practical advice for inhabitants of these areas, but some research has shown that wearing protective clothing and cleaning wounds immediately may be beneficial.6

Because prevention of infection is impossible without knowing the mode of disease transmission, control of Buruli ulcer centers around education about the clinical signs of the disease so that it can be treated before massive disfigurement. The World Health Organization (WHO) has released control guidelines that outline a strategy for strengthening the infrastructure of local health systems to ensure timely and effective case management.7

Due to the growing importance of the disease and lack of existing research, the WHO developed the Global Buruli Ulcer Initiative (GBUI) in 1998 to promote research and develop control strategies for Buruli.8

Existing Products

Drugs

While no drugs have been specifically developed to treat M. ulcerans infection, rifampicin and streptomycin in combination dramatically heal lesions after 8 weeks of treatment with only 3% recurrent infections.5 Until recently, treatment of Buruli ulcer generally focused on surgical excision of the lesion to avoid spreading the infection deeper into the tissue. In rural and impoverished areas, surgery as treatment for Buruli ulcer is impractical. Surgical treatment is also associated with a higher recurrence rate (6-28%) as compared to antibiotic treatment (less than 2%).5 Therefore, the WHO guidelines recommend 8 weeks of rifampicin-streptomycin drug combination, with surgery only as necessary.2

Vaccines

There are currently no vaccines in use to prevent Buruli ulcer. Some studies suggest that the BCG vaccine, used to prevent tuberculosis in children has some cross-protection against M. ulcerans and can prevent Buruli-related bone disease.2 However, these data are inconclusive.

Diagnostics

Diagnosis in rural endemic areas is generally based on clinical presentation, and treatment is therefore usually presumptive. However, because the nodules are usually painless and nonspecific, diagnosis often does not occur until late in the progression of the disease.6 There are few diagnostic methods to accurately detect M. ulcerans infection. Culture and smear microscopy are only 20-60% sensitive, which is insufficient for diagnosis. More sensitive methods, such as PCR, the gold standard, take longer and require laboratory resources, which limit their applicability in resource-limited areas.9

References

  1. WHO. “Buruli Ulcer”.
  2. Wansbrough-Jones M et al. (2006). “Buruli Ulcer: emerging from obscurity.” The Lancet 367:1849-1858
  3. WHO (2010). “Buruli ulcer endemic countries”.
  4. Merritt R et al (2005). “Unraveling an emerging disease associated with disturbed aquatic environments: the case of Buruli ulcer”. Frontiers in Ecology and the Environment 3: 323-331
  5. Portaels F et al. (2009). “Buruli Ulcer”. Clinics in Dermatology 27: 291-305
  6. Sizaire V et al. (2006). “Mycobacterium ulcerans infection: control, diagnosis, and treatment”. Lancet Infectious Disease 6: 288-296
  7. WHO. “Objective and strategy for control and research".
  8. WHO. “The history of GBUI".
  9. WHO (2007). Buruli ulcer disease. Fact sheet No. 199

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Drugs

Analysis

Drug treatment of Buruli ulcer was recommended relatively recently. Although first line treatment with rifampicin and streptomycin is most common, experimental substitutions of other antibiotics are being evaluated.1 Because M. ulcerans is biologically related to other mycobacteria, including the bacteria that cause leprosy and tuberculosis, there may be opportunities to repurpose products in development across these diseases.

Vaccines

Analysis

Vaccine targets for Buruli ulcer are difficult to pinpoint, primarily because it is still unclear whether M. ulcerans is an intracellular or an extracellular pathogen. Mycolactone, the bacteria’s toxin, would be a clear target for a vaccine, but no antibodies against the toxin have been detected in the sera of Buruli patients. Because data suggests that the tuberculosis BCG vaccine protects against Buruli infection, some researchers hypothesize that an M. ulcerans live attenuated vaccine could be effective for preventing infection. However, live attenuated vaccines have not been formally explored. Subunit and DNA vaccines encoding Ag85A were evaluated in a mouse model. These vaccines produced comparable or lesser immunogenicity to M. ulcerans when compared to the tuberculosis BCG vaccine in a mouse model.2 Hsp65 did not limit the progression of the disease, and was considered inferior to BCG.3 Ag85A is also in testing as a tuberculosis vaccine, and the 91% homology between the antigens may allow for a vaccine that is effective against both diseases.4 Indeed, any vaccines in development for the prevention of infection with tuberculosis should be evaluated for potential cross-protection against M. ulcerans.

Diagnostics

Analysis

The WHO defines the development of a rapid diagnostic test for Buruli ulcer disease as a top priority.5 In order to improve treatment outcomes, a test that would detect infection before development of the nodule would be especially useful.5 A mycolactone based serology test is now in clinical evaluation. However, protein antigen test development is still in the antigen validation stage.6 There have been prior challenges finding antibodies to mycolactone, an obvious diagnostic target. There continue to be challenges in finding proteins that are unique to M. ulcerans.5

References

  1. Walsh D et al (2010). “Recent advances in leprosy and Buruli ulcer (Mycobacterium ulcerans infection.” Current Opinion in Infectious Diseases 23: 445-455
  2. Huygen K et al (2009). “Buruli ulcer disease: prospects for a vaccine.” Medical Micobiology and Immunology 198: 69-77
  3. Coutanceau E. et al (2006). “Immunogenicity of Mycobacterium ulcerans Hsp65 and protective efficacy of a Mycobacterium leprae Hsp65-based DNA vaccine against Buruli ulcer.” Microbes and Infection 8(8).
  4. Tanghe et al (2008). Improved Protective Efficacy of a Species-Specific DNA Vaccine Encoding Mycolyl-Transferase Ag85A fromMycobacterium ulcerans by Homologous Protein Boosting. PLoS NTDs 2(3)
  5. WHO (2007). Buruli ulcer disease. Fact sheet No. 199
  6. Pidot S.J. et al. (2010) “Serological Evaluation of Mycobacterium ulcerans antigens indentified by comparative genomics.” PLoS Negl. Trop. Dis. 4(11) e872

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The following series of tables describe the availability of tools for research, discovery, and development of novel drugs, vaccines, and diagnostics for Mycobacterium ulcerans, the causative agent of Buruli ulcer. The tools listed in the following tables are not intended to be an all-inclusive list but rather capture the most common tools used for drug, vaccine, and diagnostic development. The most promising tool for M. ulcerans is a bioluminescent strain of bacteria that can be used for in vitro and in vivo studies.

Drugs Development Tools

Basic Research: Target IdentificationTarget ValidationScreening: Hit/Lead Identification OptimizationPre-clinical ValidationClinical Validation

Genome: Sequenced & annotated (M. ulceransAgy99)1

Key databases:
GenoList8
GenBank: Accession #CP0003251

In vitro culture: M. ulcerans can be cultured on standard mycobacteriological media. Very slow growing5. Optimal incubation temperature 30-32°C (lower than M. tuberculosis)1,2,3,5

Gene knock-outs:Possible, but not common (allele exchange reported in very closely related M. marinum strain)4

Conditional gene knock-outs: Possible, but not common (Site-specific recombination mediated by mycobacteriophage L5 integrase successful for integration of genetic material into M. ulceranschromosome.)5(Extrachromosomal plasmid stable & compatible with endogenous giant virulence plasmid pMU001 in M. ulcerans.)5

Transposon mutagenesis: Yes10,11

RNAi: No 

Other antisense technology:  No 

Viability assays:  Viability can be assessed using in vitro culture of bacteria.  

Transcription microarrays: Yes (plasmid-based covering 10% of genome)7

Proteomics: Yes6 

Crystal structures:  Yes (MetB: cystathionine gamma-synthase)9

Whole-cell screening assays: Yes5

Enzymatic screening assays: Possible, but not common

Animal models:Yes12,13,14

Monitoring treatment efficacy:Yes15,16,17,18 

Availability of endpoints: Yes, lesion healing/complete re-epithelialization 1 year after treatment start with no recurrence and without surgical debridement1

Availability of surrogate endpoints: Yes, time to complete wound healing & time to complete wound coverage by a crust15

Access to clinical trial patients/sites:  Limited

Vaccines Development Tools

Basic Research: Antigen IdentificationImmune Response CharacterizationClinical Validation

See drug development tools above

Predictive animal models: Yes, mouse model19 

Detection of endogenous antigen specific response in clinical samples:Yes20,22

Natural immunity well characterized:Yes20,21

Surrogate markers of protection: Yes, RLU production of bioluminescent strain in mouse footpad model12 

Challenge studies possible: Yes, mouse model12,14

Diagnostics Development Tools

Basic Research: Biomarker IdentificationBiomarker ValidationClinical Validation

See drug development tools above

Biomarkers known: Yes, Mycolactone in patient serum23; Six specific antigens identified by comparative genomes that allowed identification of exposure to M. ulcerans25 

Access to clinical samples: Limited, Multiple site research teams described at www.stopburuli.org but patient numbers low

Possible sample types: Unknown

Access to clinical trial patients/sites: Limited,www.stopburuli.org lists research teams but patients numbers low 

Treatment available if diagnosed: Yes

References

  1. Stinear, T. P., Seemann, T., Pidot, S., et al. (2007) Reductive evolution and niche adaptation inferred from the genome ofMycobacterium ulcerans, the causative agent of Buruli ulcer. Genome Res. 17:192-2000.
  2. Portaels, F., et al. (2009) Buruli ulcer. Clinics in Dermatology 27:291-305.
  3. Eddyani, M., and F. Portaels. (2007) Survival of Mycobacterium ulcerans at 37°C. Clin. Microbiol. Infect. 13:1033-1035.
  4. Pidot, S. J., et al. (2010) Regulation of the 18 kDa heat shock protein in Mycobacterium ulcerans: an alpha-crystallin orthologue that promotes biofilm formation. Mol. Microbiol. 78(5):1216-1231.
  5. Zhang, T., et al. (2010) Rapid assessment of antibacterial activity against Mycobacterium ulcerans by using recombinant luminescent strains. Antimicrob. Agents. Chemother. 54(7):2806-2813.
  6. Tafelmeyer, P., et al (2008) Comprehensive proteome analysis of Mycobacterium ulcerans and quantitative comparison of mycolactone biosynthesis. Proteomics. 8(15):3124-3128.
  7. Rondini, S., et al. (2007) Ongoing genomic reduction in Mycobacterium ulceransEmerg. Infect. Dis. 13(7):1008-1015.
  8. Lechat, P., et al. (2008) GenoList: an integrated environment for comparative analysis of microbial genomes. Nucleic Acids Res. 36(Database issue):D469-474.
  9. Clifton, M. C., et al. (2011) Structure of the cystathionine gamma-synthase MetB from Mycobacterium ulceransActa Crystallogr Sect F Biol Cryst Commun. 67(Pt 9):1154-8.
  10. Stinear, T. P., et al. (2004) Giant plasmid-encoded polyketide synthases produce the macrolide toxin of Mycobacterium ulceransPNAS. 101(5):1345-1349.
  11. Rubin, E. J., et al. (1999) In vivo transposition of mariner-based elements in enteric bacteria and mycobacteria. Proc Natl Acad Sci USA96(4):1645-1650.
  12. Zhang, T., et al. (2011) Using bioluminescence to monitor treatment response in real time in mice with Mycobacterium ulcerans infection. Antimicrob Agents Chemother55(1):56-61.
  13. Dega, H., et al. (2002) Bactericidal activity of rifampin-amikacin against Mycobacterium ulcerans in mice. Antimicrob Agents Chemother. 46(10): 3193-6.
  14. Shepard, C. C., (1960) The experimental disease that follows the injection of human leprosy bacilli into foot pads of mice. J. Exp. Med. 112:445-454.
  15. Nienhuis, W. A., et al. (2010) Antimicrobial treatment for early, limited Mycobacterium ulcerans infection: a randomized controlled trial. Lancet375(9715):664-72.
  16. Ruf, M-T., et al. (2011) Histopathological changes and clinical responses of Buruli ulcer plaque lesions during chemotherapy: A role for surgical removal of necrotic tissue? PLos Negl Trop Dis 5(9): e1334. doi:10.1371/journal.pntd.0001334.
  17. Schutte, D., et al. (2007) Development of highly organized lymphoid structures in Buruli ulcer lesions after treatment with rifampicin and streptomycin. PLoS Negl Trop Dis 1: e2. doi:10.1371/journal.pntd.0000002.
  18. O’Brian, D. P., et al. (2009) “Paradoxical” immune-mediated reactions to Mycobacterium ulcerans during antibiotic treatment: a result of treatment success, not failure. Med J Aust 191:564-566.
  19. Converse, P. J., et al. (2011) BCG-mediated protection against Mycobacterium ulcerans infection in the mouse. PLoS Negl Trop Dis5(3):e985.
  20. Huygen, K., et al. (2009) Buruli ulcer disease: prospects for a vaccine. Med Microbiol Immunol198:69-77.
  21. Silva, M. T., et al. (2009) Pathogenetic mechanisms of the intracellular parasite Mycobacterium ulcerans leading to Buruli ulcer.Lancet Infect Dis9(11):699-710.
  22. Zavattaro, E., et al. (2010) Serum cytokine profile during Mycobacterium ulcerans infection (Buruli ulcer).
  23. Sarfo, F.S., et al. (2011) Mycolactone diffuses into the peripheral blood of Buruli ulcer patients-implications for diagnosis and disease monitoring. PLoS Negl Trop Dis5(7):e1237.
  24. www.stopburuli.org
  25. Pidot SJ, Porter JL, Marsollier L, Chauty A, Migot-Nabias F, et al. (2010) Serological Evaluation of Mycobacterium ulceransAntigens Identified by Comparative Genomics. PLoS Negl Trop Dis 4(11): e872. doi:10.1371/journal.pntd.0000872

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To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs.