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Antigenic variation

African trypanosomes including the species Trypanosoma brucei are single-celled parasites of the blood. T.┬ábrucei kills ~50 000 people annually in sub-Saharan Africa and related parasites cause a wasting disease of cattle called n'gana which has a major detrimental economic impact in the same areas. The organism is transmitted by the bite of the tsetse fly, and is unusual in parasitizing the bloodstream in an exclusively extracellular form – effectively in full view of the immune system. This feat is achieved through the expression of a series of immunologically-distinct cell surface coats – a process that is known as antigenic variation.

antigenic variation
Antigenic variation in Trypanosoma brucei parasites. Trypanosomes can be see amongst red blood cells. The cells have been stained with markers for: the dominant VSG (magenta), general cell surface (orange), DNA (green). Arrow highlights a cell that has switched to the expression of an alternative VSG type.

Antigenic variation is fundamental to African trypanosome pathogenicity because it is both the parasite's major mechanism of immune evasion and also a strategy for the maintenance of a chronic infection that maximises the chances of transmission to a new host. Trypanosome antigenic variation is also an 'extreme' example of a strategy of immune evasion used to some extent by a great number of parasites and pathogens (including malaria parasites, Giardia, Borrelia, Neisseria and HIV), and understanding how trypanosomes achieve it is relevant to many diseases.

Genome structure

The organisation of the Trypanosoma brucei genome is highly adapted to the organism's parasitic lifestyle. It is also different from many model systems because of the great evolutionary distance between trypanosomes and yeast or man. The chromosomes can be divided into 3 classes: megabase chromosomes, intermediate chromosomes and minichromosomes. Megabase chromosomes are diploid and consist of 11 homologous pairs. These chromosomes contain all of the 'housekeeping' genes, which are arranged into large polycistronic transcription units of apparently functionally unrelated genes.

The karyotype of Trypanosoma brucei demonstrated by pulsed-field gel electrophoresis of whole-chromosome sized DNAs. The chromosomes can be divided into 3 classes: megabase-sized chromosomes (MBCs), intermediate-sized chromosomes (ICs) and numerous minichromosomes (MCs). The MCs and ICs are highly enriched in a specific 177 bp repeat. Extract from Wickstead et al. (2004) Genome Res 14:1014-24.

Unlike the large chromosomes, the intermediate and minichromosomes are aneuploid and are involved in immune evasion. A typical trypanosome cell contains ~100 of these specialised chromosomes and they carry a library of VSG genes in telomeric sites which are used for antigenic variation. Both intermediate and minichromosomes are built around a common repetitive core with inverted symmetry. We are interested in how the genome organisation of trypanosomes evolved, how it is maintained and how it is used during antigenic variation.

minichromosome structure
A cartoon illustrating the structure of the MCs showing the repetitive palindrome common to all the small chromosomes. Extract from Wickstead et al. (2004) Genome Res 14:1014-24.