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Mycobacterium ulcerans

M. ulcerans is an emerging pathogen that causes Buruli ulcer, a debilitating cutaneous infection that is reaching epidemic proportions in parts of West Africa (Johnson et al. 2005). Buruli ulcer is considered to be the third most common mycobacterial disease of nonimmunocompromised persons, after tuberculosis and leprosy. M. ulcerans, unlike other mycobacterial pathogens, produces a macro-lide toxin, mycolactone (George et al. 1999). Treatment of the disease is usually by surgical excision of infected and surrounding tissue, as the organism in situ is unresponsive to drug therapy. For a long time the mode of transmission of M. ulcerans has been unknown. However, recent investigations proposed a transmission chain involving biofilms on water plants, snails, and aquatic insects (Mar-sollier et al. 2002, 2004). It has been shown that M. ulcerans can multiply to very high numbers in the salivary glands of water insects and can then be transmitted by bites to the mammalian host. Recent detection of M. ulcerans-specific DNA

sequences in water from swamps in south-east Australia and aquatic insects in Benin have confirmed that it is primarily an environmental organism with a temperature optimum of 32 °C.

In contrast to M. leprae, the genome of M. ulcerans is nearly 1.5 Mbp larger than that of M. tuberculosis, with a predicated size of approximately 6 Mbp (http:// genopole.pasteur.fr/Mulc/BuruList.html). This is close to that of the related fish pathogen M. marinum, which also has an estimated genome size of approximately 6.7 Mbp (http://www.sanger.ac.uk/Projects/M_marinum/). While the annotation of the complete M. ulcerans genome has not been finished at the time of writing, during the genome sequencing project a 170-kbp plasmid was identified that carries the pks genes encoding the large polyketide synthases needed for the synthesis of the mycolactone toxin. This is in contrast to the M. tuberculosis complex, in that with M. ulcerans the main virulence factor is a plasmid-encoded toxin, most probably acquired by horizontal transfer. Otherwise the organism resembles M. marinum, which - for the human host - is an opportunistic pathogen and a much lesser concern for public health than M. ulcerans.

In a recent study, investigation of several isolates of M. ulcerans showed that parts of the toxin-encoding plasmid may be lost, probably due to recombination between the highly repetitive sequences of the pks genes (Stinear et al. 2004). However, as this loss of function is related to the loss of virulence, it probably occurred during in vitro culture. However, such partial loss of the plasmid by certain M. ulcerans strains may contribute to the finding that the incidence and location of Buruli ulcer cases in a given geographical location may vary extensively, i.e., certain strains may disappear as a source for human infection due to the loss of parts of the plasmid (Stinear et al. 2005). In addition, future comparative genome analyses of the now available complete sequences will reveal whether M. ulcerans also has chromosomally encoded factors that are necessary for the production of mycolactone, providing greater insight into the evolutionary mechanisms which gave rise to this fascinating mycobacterium.

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