Mycobacterium ulcerans causes
Buruli ulcer, a neglected tropical
skin disease manifesting as chronic
wounds that can leave victims with major, life-long
deformity and disability. Differently from other mycobacterial pathogens, M ulcerans produces
mycolactone, a diffusible
lipid factor with unique cytotoxic and immunomodulatory properties. Both traits result from
mycolactone targeting Sec61, the entry point of the secretory pathway in eukaryotic cells. By inhibiting Sec61,
mycolactone prevents the host cell's production of secreted
proteins, and most of its transmembrane
proteins. This molecular blockade dramatically alters the functions of immune cells, thereby the generation of protective immunity. Moreover, sustained inhibition of Sec61 triggers proteotoxic stress responses leading to apoptotic cell death, which can stimulate vigorous immune responses. The dynamics of bacterial production of
mycolactone and elimination by infected hosts thus critically determine the balance between its immunostimulatory and immunosuppressive effects. Following an introduction summarizing the essential information on
Buruli ulcer disease, this review focuses on the current state of knowledge regarding
mycolactone's regulation and biodistribution. We then detail the consequences of
mycolactone-mediated Sec61 blockade on initiation and maintenance of innate and adaptive immune responses. Finally, we discuss the key questions to address in order to improve immunity to M ulcerans, and how increased knowledge of
mycolactone biology may pave the way to innovative
therapeutics.