Antigenic variation in African trypanosomes

Abstract

Studies on Variant Surface Glycoproteins (VSGs) and antigenic variation in the African trypanosome, Trypanosoma brucei, have yielded a remarkable range of novel and important insights. The features first identified in T. brucei extend from unique to conserved-among-trypanosomatids to conserved-among-eukaryotes. Consequently, much of what we now know about trypanosomatid biology and much of the technology available has its origin in studies related to VSGs. T. brucei is now probably the most advanced early branched eukaryote in terms of experimental tractability and can be approached as a pathogen, as a model for studies on fundamental processes, as a model for studies on eukaryotic evolution or often all of the above. In terms of antigenic variation itself, substantial progress has been made in understanding the expression and switching of the VSG coat, while outstanding questions continue to stimulate innovative new approaches. There are large numbers of VSG genes in the genome but only one is expressed at a time, always immediately adjacent to a telomere. DNA repair processes allow a new VSG to be copied into the single transcribed locus. A coordinated transcriptional switch can also allow a new VSG gene to be activated without any detectable change in the DNA sequence, thereby maintaining singular expression, also known as allelic exclusion. I review the story behind VSGs; the genes, their expression and switching, their central role in T. brucei virulence, the discoveries that emerged along the way and the persistent questions relating to allelic exclusion in particular.

Keywords: Immune evasion; In situ; Monoallelic; Polycistronic; Silencing; Trans-splicing.

Graphical abstract

Fig. 1

VSG expression and switching. (A) VSG switching brings about antigenic variation. Combined with successive immune responses, this can generate a relapsing parasitaemia. Natural infections are more complex than this highly simplified schematic. (B) Studies on VSG expression revealed some unusual features. The single expressed VSG was found to be flanked by distinct repetitive sequences. Three further unusual features are indicated (boxes).

Fig. 2

DNA recombination is central to VSG switching. The active subtelomeric VSG locus is prone to spontaneous DNA breaks. Three classes of repair templates are shown with VSGs represented as coloured boxes; those sharing more (flanking) homology with the active site are used more frequently (grey arrows). The homologous sequences indicated are the 70-bp repeats (blue stripes), the telomeric repeats (black stripes), the VSG 3′-UTRs (thick black bars) and a portion of the VSG coding sequence (red). A break in or around the active VSG is followed by DNA resection extending towards the 70-bp repeats, often initiating recombination in this region.

Fig. 3

VSG allelic exclusion is not yet understood. (A) Only one of the telomeric VSGs (red and green) is active and only in the mammalian stages. This associates with a focus of extranucleolar RNA Pol I and other factors (light blue) and produces the VSG coat (outer red box). The ‘+’ and ‘x’ symbols indicate the active and silent telomeres, respectively. (B) Transcription can occasionally switch from one telomeric VSG to another; a coordinated epigenetic switch maintains allelic exclusion. The dashed arrow indicates transcription. Other details as in A.