Mycolactone is a polyketide-derived macrolide produced by Mycobacterium ulcerans, the causative agent of Buruli ulcer (BU) disease, a tropical skin disease that represent the third most common mycobacteriosis after Tuberculosis and Leprosy. Mycolactone plays a critical role in bacterial virulence and is sufficient to induce BU-like lesions that are marked by an intriguing combination of tissue necrosis, defective pain and lack of inflammation. Recently, we and others have identified the Sec61 translocon as the host receptor mediating the anti-inflammatory and cytotoxic effects of mycolactone.
Using M. ulcerans infected mice and samples from BU patients, we have previously shown that mycolactone diffuses beyond the site of infection. However, if we know that mycolactone is able to diffuse systemically in the organism, how it travels in biological fluids, how it is delivered to cells and released is currently unknown. These questions are crucial in a translational perspective but would also be important in the context of the disease to prevent toxin delivery.
The project will aim at exploring the biodistribution of mycolactone in vivo, the contribution of lipid carriers to mycolactone systemic diffusion and the possibility that mycolactone entry/ release into/ by cells could involve specific receptors.
This work will provide crucial information in a perspective of therapeutic use of mycolactone but also for the management of BU disease. Indeed, if the currently used antibiotherapy leads to the elimination of the bacteria and to the arrest of mycolactone production, we do not have any mean to impair mycolactone deleterious effects. Since there is currently no blocking antibody against mycolactone, a strategy would consist in preventing mycolactone diffusion inside the cells. To this end, we will have to understand how mycolactone diffuses, enter and is released by the cells.
The candidate is expected to have experience in cell culture, experience with FACS analysis would be a plus.