Unravelling trypanosome antigenic variation mechanisms.

Abstract

African trypanosomes evade the immune response of their mammalian hosts by antigenic variation of their surface coat, which comprises variant surface glycoproteins (VSG). Two main factors account for this variation: (1) replacement of the transcribed VSG gene in the active telomeric expression site by a different VSG gene and (2) switching of the active expression site (ES) among, in the case of Trypanosoma brucei, the 20 or so different possible ES. However, the mechanism by which the parasite switches between active ES has been the subject of much conjecture (cross-talk vs non-cross-talk models). Chaves et al. showed that the actively transcribed VSG expression site was not located in the nucleolus [1xSubnuclear localization of the active variant surface glycoprotein gene expression site in Trypanosoma brucei. Chaves, I et al. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 12328–12333Crossref | PubMed | Scopus (51)See all References][1]. They also suggested that such transcription units were transcribed by an RNA polymerase with the characteristics of Pol I, an enzyme normally (at least in mammalian cells) confined to the nucleolus. They raised the possibility that transcription outside the nucleolus might involve the ES being attached to a special nuclear substructure. This led them to suggest that, ‘Such a unique location accommodating only a single active VSG ES would help to explain why only one VSG ES can be active at a time’. However, without a way of localizing the active ES to the proposed ‘special nuclear substructure’, the exact mechanism of ES switching remained unproven.It is in this context that Navarro and Gull have been able to demonstrate, for the first time, the existence of a Pol I-containing extranucleolar expression site body (ESB), which appears to act as a focus for the active ES, by using a combination of RNA fluorescence in situ hybridization, green fluorescent protein (GFP) tags and high-quality microscopic images [2xA pol I transcriptional body associated with VSG mono-allelic expression in Trypanosoma brucei. Navarro, M and Gull, K. Nature. 2001; 414: 759–763Crossref | PubMed | Scopus (174)See all References][2]. Significantly, their results show that, whereas the ESB is present in bloodstream-form trypanosomes, it is absent from procyclic tsetse-form trypanosomes, which express a different invariant surface glycoprotein, procyclin. The presence of the ESB in bloodstream forms and its apparent resistance to DNA digestion are highly indicative of the existence of a ‘coherent architectural body’. The authors have also detected ESB in post-mitotic nuclei during parasite division, suggesting that the ESB is replicated along with the active ES in each daughter trypanosome. Such a process would allow the active transcriptional state to be maintained and inherited in dividing parasites and provides a model by which a single VSG type might predominate in a parasitemic wave.Finally, the existence of an ESB provides the basis for a model explaining antigenic switching according to the cross-talk hypothesis, namely a system in which only the single active ES can be present within the ESB, all other inactive ES being excluded from the structure. However, there remains some work to be done; as the authors conclude, the specific mechanism that ensures that only one ES occupies the ESB is still unknown.