The significance of duplicative VSG gene activation during antigenic variation in African trypanosomes

Robinson, Nick (1999) The significance of duplicative VSG gene activation during antigenic variation in African trypanosomes. PhD thesis, University of Glasgow.

Abstract

African trypanosomes can survive prolonged exposure to the immune responses of their mammalian hosts by constantly changing the variant surface glycoprotein (VSG) expressed in their surface coat in a process known as antigenic variation. Each parasite has a repertoire of approximately 1000 silent VSG genes, which are expressed differentially. The VSG genes are expressed exclusively at specialised transcriptional units known as the bloodstream expression sites (BBSs). Approximately 20 of these sites exist in the trypanosome nucleus, although only one is maximally active at a time, ensuring that a single VSG is expressed in the parasite's surface coat. VSG switching is mediated by replacing the VSG gene in the active BES, or by silencing the active BES and initiating transcription from a new BES. Investigations into trypanosome antigenic variation have described several different VSG switching mechanisms, although the majority of these studies were performed with laboratory attenuated trypanosome lines. Following repeated syringe passaging, these "monomorphic" lines have lost the ability to differentiate from the proliferative bloodstream form. Under normal circumstances these trypanosomes cannot be transmitted by the tsetse fly and do not develop through their life cycle. In addition, monomorphic trypanosomes display a marked reduction in their VSG switch rates, which are up to 4 or 5 orders of magnitude lower than those of non-adapted lines. This raises questions about the significance of the switching mechanisms observed in these lines. It has been proposed that non-adapted, or pleomorphic, trypanosomes normally have an active VSG switch mechanism, involving gene duplication, that is depressed, or from which a component is absent, in monomorphic lines. The main aim of this thesis was to examine this hypothesis by analysing the switching mechanisms used during VSG activation during the early stages of a chronic, pleomorphic infection. Additionally, this investigation examined the chromosomal environment of the basic copy VSG genes, to determine whether a chromosome position effect influenced the early order of VSG gene expression. It appears that, during the early stages of infection, trypanosome antigenic variation is predominated by duplicative transposition of telomeric VSGs, many of which reside on the minichromosomes. These results contrast strongly with the outcome of analyses of monomorphic trypanosomes, which utilize several different switching mechanisms, and most commonly display transcriptional switching during the early stages of infection. The work presented in this thesis therefore supports the hypothesis of a dedicated duplicative switching mechanism that is reduced in (or even absent from) laboratory adapted, monomorphic lines.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Colleges/Schools: College of Medical Veterinary and Life Sciences
• Supervisor's Name: Barry, Prof. Dave
• Date of Award: 1999
• Depositing User: Enlighten Team
• Unique ID: glathesis:1999-38928
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 16 Nov 2018 12:07
• Last Modified: 26 Oct 2022 08:45
• Thesis DOI: 10.5525/gla.thesis.38928
• URI: https://theses.gla.ac.uk/id/eprint/38928

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