Mycolactone is the lipid toxin that causes tissue necrosis (cell death) and immunosuppression (lack of immune response) in the neglected tropical disease, Buruli ulcer. These devastating ulcers  are caused by infection with Mycobacterium ulcerans, which makes tissue-diffusible mycolactone during its growth.
Research in my laboratory seeks to understand the molecular mechanism behind mycolactone’s effects on host cells. Recently we made a major breakthrough in this area  when we discovered that it prevents the translocation of proteins into the endoplasmic reticulum (ER) by inhibiting the action of the Sec61 translocon. This is a fundamental system of cell biology that acts as a channel separating the ER from the cytosol, and a large proportion of proteins undergo translocation during their biosynthesis. Surprisingly there are still major gaps in our knowledge of how translocation occurs.
We already know that one consequence of mycolactone action is that some blocked proteins are rapidly destroyed by the cell, and so biosynthesis effectively stops. Furthermore, the longer the exposure lasts, more and more normal cellular processes start to break down. This project will seek to better understand the cellular consequences of translocation blockade by mycolactone by delineating pathways that lead to cell death.
This project will offer a world-class training in molecular biology and cell biology – techniques in routine use in the lab include tissue culture, western blotting, quantitative real-time PCR, confocal/fluorescent microscopy, translational profiling, microarrays, flow cytometry, mass spectrometry, HPLC, translocation assays, as well as CRISPR technology for genome editing.
1. https://www.youtube.com/watch?v=W0Gu3kNE_9c 2. Hall BS, Hill K, McKenna M, Ogbechi J, High S, Willis AE & Simmonds RE. (2014) The pathogenic mechanism of the Mycobacterium ulcerans virulence factor, mycolactone, depends on blockade of protein translocation into the ER. PLoS Pathogens: 10, e4