Molecular mechanisms mediating immune evasion in African trypanosomes. (360G-Wellcome-095161_Z_10_Z)

1\. Our main aim is to elucidate transcriptional control in African trypanosomes, including how VSG expression sites (ESs) are regulated. What is the role of chromatin remodeling in T. brucei? How are ESs activated in a strictly monoallelic fashion? Which proteins mediate life-cycle specific differences in ES transcriptional control in bloodstream and insect form T. brucei? We will answer these questions through a functional analysis of T. brucei proteins which we have recently disc overed are involved in transcriptional control, including TbISWI, NLP, FACT, NAP1 and histone H1 in the first instance. We will also investigate the functional architecture of ESs, including potential regulatory roles for flanking regions of simple sequence repeats. 2. Our second aim is to understand how VSG protects the trypanosome from the mammalian immune system, and determine how VSG synthesis is monitored during the T. brucei cell cycle. We have found that VSG is essential, an d blocking its synthesis triggers an abrupt cell cycle arrest immediately before cytokinesis. We will dissect the mechanism behind this cell cycle checkpoint. What aspect of VSG is sensed during trypanosome cell cycle progression? We will investigate how VSG protects the trypanosome from the mammalian complement system.