Molecular mechanisms mediating immune evasion in African trypanosomes

The African trypanosome Trypanosoma brucei is an extraordinarily effective extracellular pathogen. Key for its survival is a protective Variant Surface Glycoprotein (VSG) coat, which is expressed at an extraordinarily high level from a VSG gene located in an RNA polymerase I transcribed VSG expression site. Although an individual trypanosome has multiple bloodstream form expression sites, stringent mono-allelic exclusion ensures that only one is transcribed at a time. We would like to understand how this mono-allelic exclusion operates. We have generated T. brucei strains with disrupted mono-allelic exclusion, which dynamically switch between two different expression sites. What restriction has disappeared? T. brucei additionally contains metacyclic expression sites, which are mono-allelically expressed in the relevant life-cycle stage. How are these different types of expression sites controlled? We have recently made the striking discovery that blocking trans-splicing leads to an abrupt halt in transcription of the active VSG expression site. How does RNA processing feed back to control this unusual RNA polymerase I transcription unit? Last, we have discovered that VSG synthesis is sensed during the cell cycle, and blocking its synthesis triggers a precise pre-cytokinesis cell cycle arrest. How does this happen, and what stress responses are triggered?