**3. Role of mycolactone in disease progression**

Mycolactone is responsible for the necrotic nature of the disease [6, 7]. It is essentially a lipid-like toxin [6]. The exact role in the bacillus is unknown [6]. However, it is speculated to offer predatory protection from eukaryotic microorganisms [6]. Currently, 5 variants of mycolactone has been described and is grouped into A/B, C, D, E and F [53, 54]. Mycolactone A/B which is the most virulent variant is produced by *M. ulcerans* strains of African, Japan and Malaysia origin [55]. Ulcers are therefore, the most severe and difficult to treat [55]. Mycolactone C and D are localised to strains in the pacific regions, specifically Australia and China, respectively [55]. *Mycobacterium liflandii*, a West African frog pathogen produces the "E" variants [56, 57]. Mycolactone F is synthesised by *Mycobacterium pseudoshottsii* and *Mycobacterium marinum* [55].

Mycolactone has been observed to have cytopathic effect on host cells both *in vitro* and *in vivo* [6, 7, 58]. *M. ulcerans* upon entry into the body establishes a localised niche and multiplies along with mycolactone release [49]. The host mounts an initial cell-mediated response to clear the infection [49]. However, mycolactone functions as immune modulation and immunosuppressive agent [49, 59]. Thus preventing communication and recruitment of other important immune cells to the site of trauma [49, 60, 61]. Bacillus overload and dead inflammatory cells is usually seen as closed nodule-like or painless swellings (non-ulcerative). At this early stage, infection may clear or resolve naturally but persistent production of mycolactone eventually leads to necrotic and open ulcers [46, 49, 51].
