How to create coats for all seasons: elucidating antigenic variation in African trypanosomes

Abstract

Extracellular parasites of the mammalian bloodstream face considerable challenges including incessant assault by the immune system. African trypanosomes are consummate survivors in this inclement environment and are renowned for their supremely sophisticated strategy of antigenic variation of their protective surface coat during the course of chronic infections. Recent developments are making us realize how complex this antigenic machinery is and are allowing us to tackle previously intractable problems. However, many of the simplest (and arguably the most important) questions still remain unanswered!

Keywords: African trypanosome; antigenic variation; epigenetics; monoallelic exclusion; variant antigen genes; variant surface glycoprotein.

Figure 1.. Mechanisms for switching VSG.

VSG switching can be mediated through DNA rearrangements (gene conversion or telomere exchange) or transcriptional control. Duplicative gene conversion involves copying an intact VSG (A) or segments of a VSG (B) into the active VSG ES resulting in loss of the old VSG. After a telomere exchange (C), there is no loss of genetic information. A transcriptional switch entails activating a new ES and silencing the old one (D). ESs are shown with the promoters indicated with flags, VSG genes with coloured boxes, and transcription of the active ES with an arrow.

Figure 2.. Schematic of VSG expression site control mediated via opposing repressive chromatin gradients.

ESs in different activation states are shown with flags indicating the promoters, transcription with a red arrow and telomere repeats with arrow heads. Chromatin proteins and remodellers (indicated with coloured circles) help maintain a silenced chromatin state at inactive ES promoters. Telomere-binding proteins including RAP1 and TRF help maintain a repressed state at the chromosome end. These operate in a gradient extending upwards from the chromosome end, in combination with the histone methyltransferase DOT1B. The linker histone H1 coats inactivate ESs (blue circles), but upon ES activation is replaced with TDP1 (open balls), which maintains an open chromatin state. VEX1 is a marker for the active ES.