Antigenic variation and transmission of African trypanosomes. (360G-Wellcome-055558_Z_98_C)

African trypanosomes evade host specific immunity by undergoing antigenic variation, the differential expression of a family of ~1000 Variant Surface Glycoprotein (VSG) genes. Several VSG gene switching mechanisms operate in laboratory-adapted trypanosomes, which have a greatly reduced VSG switch rate, but in high-switching, non-adapted lines, we have now found there is one dominant mechanism, gene duplication, that preferentially uses telomeric genes. VSGs are first expressed in the metacyclic stage in the tsetse fly, where genes are activated by a mechanism of random selection of telomerically located promoters. Together, these findings lead to the proposal that VSG gene activation systems involve telomere silencing, which can be alleviated for individual switch events by specific, positive factors. I propose to dissect the gene duplication mechanism and its possible hierarchical nature in bloodstream trypanosomes, and the promoter activation mechanism in the tsetse fly phase. Simultaneously, basic characterization of telomere silencing has begun with a specialist laboratory, and the aim is to draw together all these strands. VSG expression is closely linked with other essential phenotypes, and I aim also to assess the nature and extent of diversity in these phenotypes in the critical metacyclic population. We specialize in study of trypanosomes in an organismal background, and the proposed studies would lead to an integrated understanding of how trypanosomes survive through programmed diversification.