The VSG expression sites of Trypanosoma brucei: multipurpose tools for theadaptation of the parasite to mammalian hosts

The variant surface glycoprotein (VSG) genes of Trypanosoma brucei are tran scribed in telomeric loci termed VSG expression sites (ESs). Despite perman ent initiation of transcription in most if not all of these multiple loci, RNA elongation is abortive except in bloodstream forms where full transcrip tion up to the VSG occurs only in a, single ES at a time. The ESs active in bloodstream forms are polycistronic and contain several genes in addition to the VSG, named ES-associated genes (ESAGs). So far 12 ESAGs have been id entified, some of which are present only in some ESs. Most of these genes e ncode surface proteins and this list includes different glycosyl phosphatid yl inositol (GPI)-anchored proteins such as the heterodimeric receptor for the host transferrin (ESAG7/6), integral membrane proteins such as the rece ptor-like transmembrane adenylyl cyclase (ESAG4) and a surface transporter (ESAG10). An interesting exception is ESAG8, which may encode a cell cycle regulator involved in the differentiation of long slender into short stumpy bloodstream forms. Several ESAGs belong to multigene families including ps eudogenes and members transcribed out of the ESs, named genes related to ES AGs (GRESAGs). However, some ESAGs (7, 6 and 8) appear to be restricted to the ESs. Most of these genes can be deleted from the active ES without appa rently affecting the phenotype of bloodstream form trypanosomes, probably e ither due to the expression of ESAGs from 'inactive' ESs (ESAG7/6) or due t o the expression of GRESAGs (in particular, GRESAGs4 and GRESAGs1). At leas t three ESAGs (ESAG7, ESAG6 and SRA) share the evolutionary origin of VSGs. The presence of these latter genes in ESs may confer an increased capacity of the parasite for adaptation to various mammalian hosts, as suggested in the case of ESAG7/6 and proven for SRA, which allows T. brucei to infect h umans. Similarly, the existence of a collection of slightly different ESAG4 s in the multiple ESs might provide the parasite with adenylyl cyclase isof orms that may regulate growth in response to different environmental condit ions. The high transcription rate and high recombination level that prevail in VSG ESs may have favored the generation and/or recruitment in these sit es of genes whose hyper-evolution allows adaptation to a larger variety of hosts. (C) 2001 Elsevier Science B.V. All rights reserved.