The VEXing problem of monoallelic expression in the African trypanosome

Abstract

The African trypanosome, Trypanosoma brucei , is a causative agent of African Trypanosomiasis (also known as “sleeping sickness” in humans and “nagana” in cattle) and imposes an enormous economic burden in regions of Sub-Saharan Africa. T. brucei is transmitted to the mammalian host through the bite of the tsetse fly. In the mammal, it survives extracellularly in the bloodstream, eventually migrating into the central nervous system and causing coma and death. To survive in the bloodstream of its mammalian host, T. brucei must evade the host immune system. The parasite is covered by a dense, variant surface glycoprotein (VSG) coat that shields other epitopes on the cell surface from antibodies produced by the host immune system (reviewed in refs. 1 and 2). A strong antibody response is mounted against the VSG upon entry of the parasite into the bloodstream. However, the parasite harbors thousands of variants of the VSG gene and periodically switches the particular variant that is expressed in a process called antigenic variation (known colloquially in T. brucei as “switching”) (1). VSG genes are transcribed from one of ∼15 telomeric bloodstream expression sites (BESs), only one of which is transcriptionally active at any given time. Transcription of VSG genes occurs within a discrete nuclear structure, called the expression site body (ESB) and is driven by Pol I (1). Switching from expression of one VSG to a new VSG can occur by multiple mechanisms, including transcriptional activation of a new BES and recombinatorial mechanisms (1). Analysis of T. brucei populations in mouse models of infection has revealed that a population of trypanosomes can contain parasites expressing as many as 66 different VSGs at any given time (3). However, although the repertoire of VSGs expressed in a population of trypanosomes is quite diverse, a single trypanosome expresses just one … [↵][1]1To whom correspondence may be addressed. Email: dschulz{at}hmc.edu or papavas{at}rockefeller.edu. [1]: #xref-corresp-1-1