Recent advances: role of mycolactone in the pathogenesis and monitoring ofMycobacterium ulceransinfection/Buruli ulcer disease

Abstract

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.

Suppressive effect of mycolactone-containing fraction from Mycobacterium ulcerans on antibody production against co-administered antigens

“…On the other hand, other researchers reported that mycolactone inhibited the function of the Sec61 translocon [7,9,26]. Sec61 mediates antigen transport across endosomal membranes and affects cross-presentation in dendritic cells [27].…”

“…WiskottAldrich syndrome protein (WASP) and neural WASP (N-WASP) were reported as direct binding targets of mycolactone [7,21]. These proteins are members of a family of scaffold proteins transducing signals involved in the dynamic remodeling of the actin cytoskeleton [22][23][24][25].…”

“…Angiotensin II type 2 receptors (AT2Rs) are also reported as mycolactone-binding proteins [7,28]. AT2R blockers inhibit Th 1 and Th 2 immune responses in mice [29,30].…”

“…Injection of mycolactone into guinea pig produced an ulcer similar to Buruli ulcer [4]. Mycolactone inhibits the production of various cytokines, chemokines, and other secreted immune modulators [7] from immune cells such as monocytes [8], macrophages [9], dendritic cells [10], and T cells [11][12][13]. When a mycolactone-deficient strain of M. ulcerans was injected into model animals, a granuloma was successfully developed and the bacteria were cleared from the infected regions [14,15], suggesting that mycolactone has a suppressive effect on cell-mediated immune responses.…”

Buruli ulcer: wound care and rehabilitation

“…The central role of mycolactone in the pathogenesis and its potential application as a biomarker for BU has been reviewed by our group. 49 …”