Mycolactone is a diffusible macrolide produced by Mycobacterium ulcerans, the causative agent of a chronic skin disease called Buruli ulcer. Defective cellular immune responses, at the local and systemic levels, are hallmarks of Buruli ulcer disease. Although extensively necrotic and infected, skin lesions show a distinctive lack of inflammatory infiltrates. Moreover, peripheral blood T cells of patients have a reduced capacity to produce IFN-gamma upon ex vivo stimulation, irrespective of the stimulus. Several lines of evidence suggest a causative role for mycolactone in all these defects. First, systemically-delivered mycolactone protects mice against chemically-induced skin inflammation. Second, the activation-induced production of cytokines by peripheral blood T cells is not altered in mice infected with mycolactone-deficient strains of M. ulcerans.
We and others reported that in vitro, mycolactone blunts the ability of immune cells to produce selected cytokines and chemokines without major effect on the cell viability. In addition, we observed that subcutaneous injection of mycolactone in mice leads to a massive T cell depletion in secondary lymphoid organs, associated with defective expression of homing receptors. Importantly, exposure of T cells to mycolactone impaired their capacity to reach draining lymph nodes upon adoptive transfer, respond to chemotactic signals and proliferate upon antigenic stimulation in situ. Today, the molecular mechanisms underlying these defects remain largely unknown, as differently from known immunosuppressors mycolactone operates post-transcriptionally and independently of mTOR and stress. One of our major goal is to understand how mycolactone targets the effector functions of immune cells, with the long term objective to develop new, mycolactone-inspired immunosuppressants.