Recent advances: role of mycolactone in the pathogenesis and monitoring of Mycobacterium ulcerans infection/Buruli ulcer disease.

Fred Stephen Sarfo,Mark Wansbrough‐Jones,Rachel E Simmonds,Richard Phillips

doi:10.1111/cmi.12547

Fred Stephen Sarfo, Mark Wansbrough‐Jones + Show 2 more

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SummaryInfection of subcutaneous tissue with Mycobacterium ulcerans can lead to chronic skin ulceration known as Buruli ulcer. The pathogenesis of this neglected tropical disease is dependent on a lipid‐like toxin, mycolactone, which diffuses through tissue away from the infecting organisms. Since its identification in 1999, this molecule has been intensely studied to elucidate its cytotoxic and immunosuppressive properties. Two recent major advances identifying the underlying molecular targets for mycolactone have been described. First, it can target scaffolding proteins (such as Wiskott Aldrich Syndrome Protein), which control actin dynamics in adherent cells and therefore lead to detachment and cell death by anoikis. Second, it prevents the co‐translational translocation (and therefore production) of many proteins that pass through the endoplasmic reticulum for secretion or placement in cell membranes. These pleiotropic effects underpin the range of cell‐specific functional defects in immune and other cells that contact mycolactone during infection. The dose and duration of mycolactone exposure for these different cells explains tissue necrosis and the paucity of immune cells in the ulcers. This review discusses recent advances in the field, revisits older findings in this context and highlights current developments in structure‐function studies as well as methodology that make mycolactone a promising diagnostic biomarker.

Highlights

Mycobacterium ulcerans (MU) infection can cause Buruli ulcer (BU), a chronic necrotizing skin infection with high prevalence in rural West Africa (Junghanss et al, 2014; O’Brien et al, 2014)
In contrast to other pathogenic mycobacteria, which are facultative intracellular pathogens of macrophages, MU is seen as extracellular clusters of bacilli lying within areas of coagulative necrosis that extend some distance from the site of bacterial colonisation (Forbes et al, 1954)
Mycolactone is known to be responsible for the immunosuppression and tissue necrosis in BU, as well as the painlessness of BU ulcers; one reason why patients often delay treatment (Goto et al, 2006)

Summary

Infection of subcutaneous tissue with Mycobacterium ulcerans can lead to chronic skin ulceration known as Buruli ulcer. Two recent major advances identifying the underlying molecular targets for mycolactone have been described It can target scaffolding proteins (such as Wiskott Aldrich Syndrome Protein), which control actin dynamics in adherent cells and lead to detachment and cell death by anoikis. It prevents the co-translational translocation (and production) of many proteins that pass through the endoplasmic reticulum for secretion or placement in cell membranes. These pleiotropic effects underpin the range of cell-specific functional defects in immune and other cells that contact mycolactone during infection. In this context and highlights current developments in structure-function studies as well as methodology that make mycolactone a promising diagnostic biomarker

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