Translocation alters the activation rate of a trypanosome surface antigen gene

Laurent, Monique; Pays, Étienne; Werf, Adrie van der; Aerts, Diane; Magnus, E; Meirvenne, N Van; Steinert, Maurice

doi:10.1093/nar/12.22.8319

Cited by 43 publications

(19 citation statements)

References 27 publications

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“…Indeed, the bacterium Anaplasma marginale, using an archival system, achieves differential switching by way of homologies in both gene flank and coding sequences (6). There is empirical support for this general trypanosome molecular mechanism (7)(8)(9)(10)(11)(12)(13)(14), and recent quantitative analysis has revealed a higher degree of order than previously supposed (15). Three studies in particular, together involving Ͼ100 variants in Ͼ50 infections, have firmly established order in VSG expression (15)(16)(17).…”

Section: T Rypanosomes Switch Antigens Primarily By Duplication Ofmentioning

confidence: 96%

Parasite-intrinsic factors can explain ordered progression of trypanosome antigenic variation

Lythgoe

Morrison

Read

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Pathogens often persist during infection because of antigenic variation in which they evade immunity by switching between distinct surface antigen variants. A central question is how ordered appearance of variants, an important determinant of chronicity, is achieved. Theories suggest that it results directly from a complex pattern of transition connectivity between variants or indirectly from effects such as immune cross-reactivity or differential variant growth rates. Using a mathematical model based only on known infection variables, we show that order in trypanosome infections can be explained more parsimoniously by a simpler combination of two key parasite-intrinsic factors: differential activation rates of parasite variant surface glycoprotein (VSG) genes and densitydependent parasite differentiation. The model outcomes concur with empirical evidence that several variants are expressed simultaneously and that parasitaemia peaks correlate with VSG genes within distinct activation probability groups. Our findings provide a possible explanation for the enormity of the recently sequenced VSG silent archive and have important implications for field transmission.mathematical model ͉ Typanosoma brucei ͉ variant surface glycoprotein ͉ switching ͉ hierarchy

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Section: T Rypanosomes Switch Antigens Primarily By Duplication Ofmentioning

confidence: 96%

Parasite-intrinsic factors can explain ordered progression of trypanosome antigenic variation

Lythgoe

Morrison

Read

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…transcription of surface antigen genes of the African trypanosome, Tipatiosoma brircei, in both mammalian bloodstream [variant surface glycoprotein (VSG) genes] [4][5][6][7][8][9] and procyclic (insect stage) trypanosomes 11 0, 1 1 J. Transcription of these genes and their transcription unit is completely insensitive to AMA in nuclear run-on analysis.…”

Section: Iiow U R I D Why Is the M -Kw; Rcpertoirt~ Predictuhle Ymentioning

confidence: 99%

Stage-specific mechanisms for activation and expression of variant surface glycoprotein genes in Trypanosoma brucei

Barry

Graham

Matthews

et al. 1990

Biochemical Society Transactions

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The African trypanosomes undergo extensive development as they proceed through their life cycle, producing a range of stages with distinct functions. In response to the somewhat treacherous, extracellular environments occupied by trypanosomes in their rather different hostsmammals and tsetse flieselaborate survival mechanisms are utilized. The best known of these is antigenic variation (reviewed in [ 1-31), Briefly, the bloodstream form trypanosomes and the metacyclic stage are coated by a layer of the variant surface glycoprotein (VSG). By continual switching of the VSG, the trypanosome population evades complete destruction by the specific anti-VSG immune response. There is a repertoire of more than 1000 silent VSG genes (basic copy, BC genes) in each trypanosome and these are expressed differentially by the mutually exclusive use of bloodstream expression sites (B-ES), which are located at telomeres [4, 51. Most BC genes therefore cannot be expressed where they are and are activated by duplication into B-ES, forming temporary expression-linked copies (ELCs) [6, 71. However, some BC genes normally reside at telomeres and these can be activated it1 sitir (if they occupy a silent B-ES) or by moving into another B-ES [8, 91. Each B-ES is long (at least 40 kb), as dcfined by transcriptional start regions, and contains a collection of expression-site associated genes (ESAGs), which are not related to, but are co-ordinately transcribed with, VSG genes [4,5, 101.Being essential for survival in the mammal, the VSG is first synthesized in the metacyclic stage in the tsetse fly, and it is now clear that VSG genes are activated and expressed very differently in the metacyclic and bloodstream stages.

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“…This suggests, very tentatively, that the 121 ES containing only one promoter might be activated more frequently than when the tandem promoter array is present. Deletion of the upstream promoter sequences might tag the 121 ES for future switch events, explaining why some ESs are more frequently reactivated after certain switch events (30,32).…”

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confidence: 99%

DNA Rearrangements Associated with Multiple Consecutive Directed Antigenic Switches in Trypanosoma brucei

Navarro

Cross

1996

Molecular and Cellular Biology

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Changes in variant surface glycoprotein (Vsg) expression allow Trypanosoma brucei to elude the immune response. The expressed vsg is always located at the telomeric end of a polycistronic transcription unit known as an expression site (ES). Although there are many ESs, only one is active at any particular time. The mechanisms regulating ES transcription and switching are unknown. Chromosome rearrangements within or upstream of the ES have been described to occur in occasional switch events, but no changes have been consistently associated with switching. We inserted the drug resistance genes neo and ble, conferring resistance to G418 and phleomycin, respectively, 1 kb downstream of "silent" ES promoters. This demonstrated that short-range transcription could be achieved from a silent ES promoter. From one initial transformant clone, panels of independent consecutive on-off-on switch clones were generated and analyzed. The first activation of the neo-targeted ES was always associated with deletion of the upstream tandem promoter in this ES, but no further rearrangements were detected in consecutive off-on switches of this ES. On the other hand, direct analysis of ES promoters showed that deletions and duplications occurred elsewhere. Activation of a ble-tagged 300-kb chromosome could not be achieved, but phleomycin-resistant clones could be obtained. One such clone arose from recombination between three ESs. Taken together, our experiments suggest that ES switching may occur after a period of chromosomal interactivity that may or may not leave tangible evidence in the form of detectable sequence changes.Trypanosoma brucei is an extracellular protozoan parasite that multiplies in the tissue fluids and vascular system of its vertebrate host, causing major veterinary and medical problems in Africa. The entire surface of the bloodstream form trypanosome is covered by a dense coat, which consists largely of a single molecular species known as the variant surface glycoprotein (Vsg) (8). Sequential expression of vsg genes allows the parasite to elude the immune response of the host (reviewed in references 9, 10, and 51). The expressed vsg is always located adjacent to a telomere, at the end of a polycistronic expression site (ES) (15). Hybridization analysis suggests the presence of approximately 20 ESs, whose sequences are highly conserved (13,54). Only one ES is active, yielding a single Vsg on the surface of the infective trypanosome. The ES contains a number of ES-associated genes (esag) (13, 51). ES transcription is driven by an ␣-amanitin-resistant polymerase (26, 27). The ES promoter is located 40 to 60 kb upstream of the telomeric vsg (25, 27). ES promoters sequenced so far show more than 90% sequence identity (18, 37, 53). The 5Ј end of the ES promoter is flanked by a region of imperfect direct repeats of 50 bp, which covers at least 10 kb in the vsg221 ES (54).Antigenic variation in T. brucei can occur by duplicative transposition of a new vsg into an already active ES, displacing the resident vsg. A switch in...

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Translocation alters the activation rate of a trypanosome surface antigen gene

Cited by 43 publications

References 27 publications

Parasite-intrinsic factors can explain ordered progression of trypanosome antigenic variation

Parasite-intrinsic factors can explain ordered progression of trypanosome antigenic variation

Stage-specific mechanisms for activation and expression of variant surface glycoprotein genes in Trypanosoma brucei

DNA Rearrangements Associated with Multiple Consecutive Directed Antigenic Switches in Trypanosoma brucei

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