Buruli ulcer disease: prospects for a vaccine (original) (raw)
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Trials in Vaccinology, 2016
Mycobacterium ulcerans (MU) infection causes the disfiguring necrotic skin disease, Buruli ulcer (BU). While vaccination with Mycobacterium bovis BCG provides nominal antigenic cross-reactivity for induction of immunity against experimental MU infection, a mycobacterial species with greater genetic homology to Mycobacterium ulcerans may serve as a richer source of cross-protective immunogens and lack the pathological features of MU-based vaccines. Mycobacterium marinum, a highly homologous genetic relative of MU, could be used to satisfy these criteria and, as such, we have generated a recombinant M. marinum strain expressing the immunodominant, protective MU-Ag85A. The immunogenicity and protection achieved by murine vaccination with this strain are superior to standard BCG vaccination and may serve as a foundation for developing more effective BU vaccines.
2006
Buruli ulcer caused by Mycobacterium ulcerans is of important public health problem especially in West-Africa. It is the third most common mycobacterial disease, after tuberculosis and leprosy. The World Health Organisation currently recommends the use of a combination of streptomycin and rifampicin for eight weeks before surgical excision. Stepwise implementation of this recommendation has started in some of the worst affected West African countries, including Ghana. Therefore this study was initiated to assess the susceptibility of M. ulcerans isolates from Ghana to isoniazid, rifampicin, ethambutol and streptomycin, using a microplate Alamar blue assay. Out of the 28 isolates tested, one was resistant to all four drugs analysed. All isolates with the exception of two (7.1%) and three (10.7%) were resistant to isoniazid and ethambutol respectively. On the contrary all isolates, except two (7.1%) and three (10.7%), were susceptible to rifampicin and streptomycin, respectively. This first report of rifampicin resistance in clinical M. ulcerans isolates raises major concern about antibiotic treatment modalities for Buruli ulcer.
Infection and Immunity, 2001
Buruli ulcer, caused by Mycobacterium ulcerans, is characterized by deep and necrotizing skin lesions, mostly on the arms and legs. Together with tuberculosis and leprosy, this mycobacterial disease has become a major health problem in tropical and subtropical regions, particularly in central and western Africa. No specific vaccine is available for Buruli ulcer. There is, however, evidence in the literature that suggests a cross-reactive protective role of the tuberculosis vaccine M. bovis BCG. To identify potential mechanisms for this crossprotection, we identified and characterized the M. ulcerans homologue of the important protective mycobacterial antigen 85 (Ag85A) from BCG. The homologue is well conserved in M. ulcerans, showing 84.1% amino acid sequence identity and 91% conserved residues compared to the sequence from BCG. This antigen was sufficiently conserved to allow cross-reactive protection, as demonstrated by the ability of M. ulcerans-infected mice to exhibit strong cellular immune responses to both BCG and its purified Ag85 complex. To further address the mechanism of cross-reactive protection, we demonstrate here that prior vaccination with either BCG or plasmid DNA encoding BCG Ag85A is capable of significantly reducing the bacterial load in the footpads of M. ulcerans-infected mice, as determined by Ziehl-Neelsen staining and by actual counting of CFU on 7H11 Middlebrook agar. Together, the results reported here support the potential of a cross-protective Ag85-based future vaccine against tuberculosis, Buruli ulcer, and leprosy.
PLoS neglected tropical diseases, 2016
Buruli ulcer, caused by infection with Mycobacterium ulcerans, is a chronic ulcerative neglected tropical disease of the skin and subcutaneous tissue that is most prevalent in West African countries. M. ulcerans produces a cytotoxic macrolide exotoxin called mycolactone, which causes extensive necrosis of infected subcutaneous tissue and the development of characteristic ulcerative lesions with undermined edges. While cellular immune responses are expected to play a key role against early intracellular stages of M. ulcerans in macrophages, antibody mediated protection might be of major relevance against advanced stages, where bacilli are predominantly found as extracellular clusters. To assess whether vaccine induced antibodies against surface antigens of M. ulcerans can protect against Buruli ulcer we formulated two surface vaccine candidate antigens, MUL_2232 and MUL_3720, as recombinant proteins with the synthetic Toll-like receptor 4 agonist glucopyranosyl lipid adjuvant-stable ...
Mycobacterium ulcerans Disease (Buruli Ulcer): Potential Reservoirs and Vectors
Current Clinical Microbiology Reports, 2015
Mycobacterium ulcerans is an emerging pathogen causing the skin infection Buruli ulcer (BU), one of the most neglected tropical diseases. BU is characterized by the formation of chronic, necrotizing skin lesions. This pathology is mainly attributed to the cytotoxic and immunosuppressive activities of the unique polyketide-derived macrolide toxin mycolactone secreted by the pathogen. The disease has been reported from more than 30 countries worldwide, with an extremely focal geographic distribution within endemic countries and highest incidences in remote communities of West/ Central Africa and also certain coastal areas of Australia. While M. ulcerans has long been considered an environmental bacterium, recent findings from southeastern Australia, identifying possums as probable reservoirs of infection, indicate its zoonotic potential. The exact route of M. ulcerans transmission is unclear, although it is commonly assumed that infection takes place either through physical contact with environmental reservoirs via skin abrasions or through insect bites, while direct human-to-human transmission seems to be rare.
PLoS neglected tropical diseases, 2015
Buruli ulcer, an emerging tropical disease caused by Mycobacterium ulcerans (MU), is characterized by disfiguring skin necrosis and high morbidity. Relatively little is understood about the mode of transmission, pathogenesis, or host immune responses to MU infection. Due to significant reduction in quality of life for patients with extensive tissue scarring, and that a disproportionately high percentage of those affected are disadvantaged children, a Buruli ulcer vaccine would be greatly beneficial to the worldwide community. Previous studies have shown that mice inoculated with either M. bovis bacille Calmette-Guérin (BCG) or a DNA vaccine encoding the M. ulcerans mycolyl transferase, Ag85A (MU-Ag85A), are transiently protected against pathology caused by intradermal challenge with MU. Building upon this principle, we have generated quality-controlled, live-recombinant strains of BCG and M. smegmatis which express the immunodominant MU Ag85A. Priming with rBCG MU-Ag85A followed by ...
Buruli Ulcer (Mycobacterium ulcerans Infection): a Re-emerging Disease
Clinical Microbiology Newsletter, 2009
Mycobacterium ulcerans infection is an emerging disease that causes indolent, necrotizing skin lesions known as Buruli ulcer (BU). Approximately 10% of patients develop reactive osteitis or osteomyelitis beneath skin lesions or metastatic osteomyelitis from lymphohematogenous spread of M. ulcerans. The most plausible mode of transmission is by skin trauma at sites contaminated by M. ulcerans. Pathogenesis is mediated by a necrotizing, immunosuppressive toxin produced by M. ulcerans called mycolactone. The incidence of BU is highest in children up to 15 years old and is a public health problem in countries of endemicity due to disabling scarring and bone destruction. Today, most BU occurs in West Africa, but the disease has been reported in over 30 countries. Treatment options for BU are antibiotics and surgery. BCG vaccination provides short-term protection against BU and prevents osteomyelitis. HIV seropositivity may increase the risk for BU and render BU osteomyeletis highly aggressive.
Buruli Ulcer: Advances in Understanding Mycobacterium ulcerans Infection
Dermatologic Clinics, 2011
Buruli ulcer (BU), the third most common mycobacterial infection in humans next to tuberculosis and leprosy, is an emerging infection caused by Mycobacterium ulcerans. BU is characterized by indolent, typically painless necrotizing skin lesions (Figs. 1 and 2A). Approximately 10% of patients develop bone involvement subjacent to skin lesions or metastatic osteomyelitis from lymphohematogenous spread of M ulcerans (see Fig. 2B). Pathogenesis is mediated by mycolactone, a diffusible, necrotizing, immunosuppressive, polyketidederived macrolide toxin secreted by M ulcerans. 1 In 1962, the disease was named after Buruli County, Uganda, now called Nakasongola District, where the epidemic was documented first. Other names include Bairnsdale, Kakerifu, Kasongo, or Searls' ulcer. EPIDEMIOLOGY In 1998, the World Health Organization (WHO) recognized BU as a reemerging infectious disease in West and Central Africa, with a significant public health impact. 2 The reported incidence rates of BU are highest in West Africa, especially Benin, Ghana, and Cô te d'Ivoire. However, BU is reported in about 30 countries (Fig. 3), and growing evidence suggests that BU is more widespread than earlier thought. 3 BU prevails in rural tropical wetlands, especially areas with stagnant water, including ponds and swamps. However, BU is also acquired without wetland exposure. The rapid reemergence of BU, beginning in the early 1980s, particularly in areas where people are engaged in manual agriculture in wetlands, may be attributable to the man-made alterations to the environment, such as deforestation and other topographic alterations, which increase the amount of wetlands. Changes in global temperature and precipitation patterns further promote the reemergence of BU. The WHO reports indicate that more than 5000 people are diagnosed with BU annually, but many cases are undiagnosed because of the geopolitical and socioeconomic factors in endemic countries. Children (5e15 years old) have the highest incidence of BU, with most lesions on the lower extremities. BU is a growing Disclosure: The authors have nothing to disclose. Disclaimer: The views expressed in this article are those of the author (D.S.W.) and do not reflect the official policy of the Department of the Army, Department of Defense, or the US government.
Mycobacterium ulcerans infection: control, diagnosis, and treatment
The Lancet Infectious Diseases, 2006
The skin disease Buruli ulcer, caused by Mycobacterium ulcerans, is the third most common mycobacterial disease after tuberculosis and leprosy and mainly aff ects remote rural African communities. Although the disease is known to be linked to contaminated water, the mode of transmission is not yet understood, which makes it diffi cult to propose control interventions. The disease is usually detected in its later stages, when it has caused substantial damage and disability. Surgery remains the treatment of choice. Although easy and eff ective in the early stages of the disease, treatment requires extended excisions and long hospitalisation for the advanced forms of the disease. Currently, no antibiotic treatment has proven eff ective for all forms of M ulcerans infection and research into a new vaccine is urgently needed. While the scientifi c community works on developing non-invasive and rapid diagnostic tools, the governments of endemic countries should implement active case fi nding and health education strategies in their aff ected communities to detect the disease in its early stages. We review the diagnosis, treatment, and control of Buruli ulcer and list priorities for research and development. Lancet Infect Dis 2006; 6: 288-96 Médecins Sans Frontières,
PLoS neglected tropical diseases, 2015
The only available vaccine that could be potentially beneficial against mycobacterial diseases contains live attenuated bovine tuberculosis bacillus (Mycobacterium bovis) also called Bacillus Calmette-Guérin (BCG). Even though the BCG vaccine is still widely used, results on its effectiveness in preventing mycobacterial diseases are partially contradictory, especially regarding Buruli Ulcer Disease (BUD). The aim of this case-control study is to evaluate the possible protective effect of BCG vaccination on BUD. The present study was performed in three different countries and sites where BUD is endemic: in the Democratic Republic of the Congo, Ghana, and Togo from 2010 through 2013. The large study population was comprised of 401 cases with laboratory confirmed BUD and 826 controls, mostly family members or neighbors. After stratification by the three countries, two sexes and four age groups, no significant correlation was found between the presence of BCG scar and BUD status of indi...