Mycolactone is the only identified virulence factor of Mycobacterium ulcerans, the pathogenic organism causing Buruli ulcer. While the highest rates of M. ulcerans infection in the world are found in West Africa, outbreaks of this infection (also known as Bairnsdale ulcer) occur in Australia in both coastal Victoria and far North Queensland. Infections are characterised by a nodule which usually develops into a chronic progressive ulcer if not treated. Â Mycolactone is a polyketide lactone synthesised by the mycobacteria that is both cytotoxic (high doses, extended exposure) and immunosuppressive (low doses, immediate effect). Many of the consequences of mycolactone exposure are known to involve a lack of induction, or depletion, of proteins implicated in important cellular processes, such as the immune response and cell adhesion.
We have previously shown mycolactone blocks the production of LPS-dependent proinflammatory mediators post-transcriptionally. Using polysome profiling we now demonstrate conclusively that mycolactone does not prevent translation of TNF, IL-6 and Cox-2 mRNAs in macrophages. Instead, we will provide evidence that it inhibits the production of these, along with nearly all other (induced and endogenous) proteins by a unique mechanism involving the rapid degradation of aberrantly located polypeptides. The ER and Golgi remain structurally intact and, notably, the profound loss of production of glycosylated and secreted proteins is apparent in many different disease-relevant cell types.
Our findings provide the first unifying mechanism underlying mycolactone’s observed pathological activities both in vitro and in vivo. Mycolactone-dependent inhibition of protein production not only explains the deficit of innate cytokines, but also the loss of membrane receptors, adhesion molecules and T-cell cytokines that drive the aetiology of Buruli/Bairnsdale ulcer.