M. ulcerans

Background Information

Mycobacterium ulcerans infection, widely known as Buruli ulcer (BU), is an emerging health problem in parts of the developing world and also in areas of Australia. BU was made a notifiable disease in the state of Victoria in 2004 because of a significant increase in the number of cases in several localised coastal regions. BU cases continue to present occasionally in other coastal regions of Victoria, Far North Queensland, the Northern Territory and in Papua New Guinea. Small numbers of cases have also been reported from Japan, China and Malaysia, indicating that the disease may be more widespread in the Western Pacific region than is currently recognised. In 2005, the first case of BU aquired in the state of New South Wales (NSW) was diagnosed. In Victoria, cases of BU have also been described in several marsupial species, including koalas, potoroos and possums and in 2006, the first cases in horses and a cat were documented. Progress has been made over recent years in the areas of diagnosis and treatment of BU, however knowledge on transmission and the changing epidemiology of this challenging disease is very limited. Australia is the only developed country in which there is documented active transmission of M. ulcerans. The creation of a collaborating centre in Australia, to collect and manage information on the incidence, epidemiology and control of BU in the Western Pacific Region, and to perform and coordinate appropriate research projects with the aim of determining the ecology and mode(s) of transmission of M. ulcerans to humans and animals will potentially contribute to worldwide management of BU.

Australian researchers are internationally recognised for research on BU. Notable achievements include:
• the initial culture and description of M. ulcerans and the associated infection (Bairnsdale ulcer) (1948)
• detailed descriptions of the histology and epidemiology of M. ulcerans in Australia (1990s)
• the discovery of the M. ulcerans -specific insertion sequence IS2404 (1995)
• the development of various molecular typing methods capable of distinguishing between M. ulcerans isolates from different geographic locations (1995, 2000)
• the development of a diagnostic PCR based on IS2404 (1997)
• the first detection of M. ulcerans in the environment using PCR (1997, 2000)
• the identification of the M. ulcerans plasmid carrying the genes encoding the polyketide synthases responsible for mycolactone synthesis (2004)
• the development of a suite of real-time PCR assays for the detection of M. ulcerans in clinical and environmental samples, including mosquitoes (2006).
• Sequencing and annotation of the M. ulcerans genome.

The Victorian Mycobacterium Reference Laboratory (MRL), originally known as the TB laboratory at the Fairfield Infectious Diseases Hospital, has been a department within the Victorian Infectious Diseases Reference Laboratory (VIDRL) since 1993. The MRL is responsible to the Victorian Department of Human Services for the notification of all new cases of laboratory diagnosed BU in the state of Victoria, and is responsible for entering relevant information regarding all Australian BU using a standardised epidemiological instrument (BU02).

The proposal to form the Collaborating Centre for Mycobacterium ulcerans arose from an initial invitation to A/Prof. Hayman and A/Prof. Paul Johnson from Dr. Kingsley Asiedu (Global Buruli Ulcer Initiative, WHO, Geneva). A/Prof Paul Johnson, A/Prof John Hayman and Mr John Buntine have been active members of the WHO Buruli ulcer task force since its creation in 1998.

The WHO Collaborating Centre, with the support of the MRL staff and VIDRL infrastructure, is headed by A/Prof Paul Johnson, with Dr Janet Fyfe as deputy Head. In addition, the BU Pathogenesis Research Group at Monash University, headed by Dr Tim Stinear forms an integral part of the Collaborating Centre. A/Prof John Hayman and Mr John Buntine provide additional expertise to the team.

Structure of the Collaborating Centre:

Terms of Reference:

1. To perform molecular (PCR) and culture diagnosis of Mycobacterium ulcerans infection in humans and animals for the Western Pacific Region.
2. To perform molecular typing on all new M. ulcerans isolates as an aid to epidemiological studies.
3. To systematically record and report all cases of M. ulcerans infection in Australia to the relevant state and national health authorities, and cases occuring in other countries in the the Western Pacific Region to the relevant local and national health authorities. All cases identified in the region would be reported to WHO using the BU02 standard format.
4. To gather and map the likely geographic source of infection for all cases of Buruli ulcer in the Western Pacific Region in conjunction with the Victorian Department of Human Services and contacts in Papua New Guinea.
5. To continue expanding the Centre's existing archive of isolates, histological specimens and clinical photographs for future reference and research and to continue sharing this resource with the worldwide network of M. ulcerans researchers.
6. To continue to promote, facilitate and conduct outstanding M. ulcerans research in a range of areas between local, regional and international collaborators.
7. To further develop expertise in environmental PCR in terms of providing reference, quality control, ongoing development and improvement of techniques and sharing of protocols with the M. ulcerans research community.
8. To provide ongoing excellent clinical support for the management and treatment of M. ulcerans infection in humans and and animals, both within Australia and other countries within the Western Pacific Region where cases of M. ulcerans infection are diagnosed
9. To provide training for scientists from developing countries in molecular, histological and culture diagnosis of M. ulcerans infection in humans and animals.
10. To communicate developments in the diagnosis, treatment and control of M. ulcerans infection in humans and animals to the medical, veterinary and scientific communities and the general public.
11. To provide public advocacy designed to increase awareness both locally and internationally of this important neglected disease.

Relevant recent references:

Tafelmeyer P, Laurent C, Lenormand P, Rousselle JC, Marsollier L, Reysset G, Zhang R, Sickmann A, Stinear TP, Namane A, Cole ST. (2008) Comprehensive proteome analysis of Mycobacterium ulcerans and quantitative comparison of mycolactone biosynthesis.
Proteomics. Jul 9. [Epub ahead of print]

Elsner L, Wayne J, O’Brien CR, McCowan C, Malik R, Hayman JA, Globan M, Lavender CJ, Fyfe J (2008) Localised Mycobacterium ulcerans infection in a cat in Australia. J Feline Med Surg May 19 [Epub ahead of print]

Hong H, Demangel C, Pidot SJ, Leadlay PF, Stinear T. (2008)
Mycolactones: immunosuppressive and cytotoxic polyketides produced by aquatic mycobacteria. Nat Prod Rep. Jun;25(3):447-454. Epub 2008 Apr 17

Stinear T, Johnson P. (2008) First Isolation of Mycobacterium ulcerans from an Aquatic Environment: The End of a 60-Year Search? PLoS Negl Trop Dis. 2008 Mar 26;2(3):e216

Johnson PDR, Azuolas J, Lavender CJ, Wishart E, Stinear TP, Hayman JA, Brown L, Jenkin GA, Fyfe JAM. (2007) Mycobacterium ulcerans in mosquitoes captured during outbreak of Buruli ulcer, southeastern Australia. Emerg Infect Dis 13: 1653-1660.

Fyfe JAM, Lavender CJ, Johnson PDR, Globan M, Sievers A, Azuolas J, Stinear TP. (2007) Development and application of two multiplex real-time PCR assays for the detection of Mycobacterium ulcerans in clinical and environmental samples. Appl Environ Microbiol 73: 4733-4740

Johnson PDR, Hayman JA, Quek TY, Fyfe J, Jenkin GA, Buntine JA, Athan E, Birrell M, Johnstone B, Graham J, Lavender CJ on behalf of the Mycobacterium ulcerans Study Team. (2007) Consensus recommendations for the diagnosis, treatment and control of Mycobacterium ulcerans infection (Bairnsdale ulcer) in Victoria, Australia. Med J Aust. 2007; 186 (2):64-68.

O'Brien DP, Hughes AJ, Cheng AC, Henry MJ, Callan P, McDonald A, Holten I, Birrell M, Sowerby JM, Johnson PD, Athan E.Outcomes for Mycobacterium ulcerans infection with combined surgery and antibiotic therapy: findings from a south-eastern Australian case series. Med J Aust. 2007 Jan 15;186(2):58-61.

Lavender CJ, Senanayake SN, Fyfe JA, Buntine JA, Globan M, Stinear T, Hayman JA, Johnson PD. (2007) First case of Mycobacterium ulcerans disease (Bairnsdale or Buruli ulcer) in New South Wales. Med J Aust.186 (2):62-63.