Control of gene expression in trypanosomes: Defining the nuclear lamina

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Parasitic protozoa are important agents of disease, and afflict a major proportion of the world's population. In evolutionary terms parasites are very different to their hosts, and this is frequently reflected in the presence of a great many unique or unusual mechanisms that underpin their biology. This aspect presents multiple opportunities for the understanding of pathogenesis and also the possibility of identifying therapeutic targets. In trypanosomes, which as a group cause Sleeping sickness, Chagas' disease and Kala Azar (visceral leishmaniasis) and a great many other diseases, immune evasion is vital for survival and transmission. African trypanosomes are highly reliant on antigenic variation for their longterm survival - the process is so successful that trypanosomes can infect their host for many months and in some cases years. The primary mechanism of immune evasion is antigenic variation, the periodic switching of the parasite surface through sequential expression of immunologically distinct forms of the variant surface glycoprotein (VSG). Understanding VSG expression is central to unravelling the mechanisms of trypanosome virulence and is a longstanding goal in the field. At the rim of the nucleus DNA is compacted into heterochromatin, which is transcriptionally silent and acts as a mechanism for the inactivation of genes placed there. To ensure that only one VSG is expressed at a time trypanosomes use heterochromatin as a store for all potentially expressed VSG genes except one. Recently we have uncovered a system of proteins that are localised to the rim of the trypanosome nucleus, and which regulate heterochromatin, nuclear structure and other functions. Most remarkably these proteins are distinct from those that make up the equivalent system in the host. This application proposes to interrogate in detail the manner in which the proteins comprising this system are organised, how they function and ultimately how they regulate VSG gene expression.