Control of Antigenic Variation in African Trypanosomas

Borst, Piet; Gommers-Ampt, Janet H.; Ligtenberg, M. J. L.; Rudenko, Gloria; Kieft, Rudo; Taylor, Martin C.; Blundell, Patricia A.; Leeuwen, Fred van

doi:10.1101/sqb.1993.058.01.014

Cited by 29 publications

(12 citation statements)

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“…6). This comparison also indicates a region of hypervariability at amino acid positions 151-169, an observation also noted by Borst et al (47) for other ESAG 6 and 7 amino acid sequences.…”

Section: ␣-Amanitin Since In Other Experiments It Repeatedly Was Unafsupporting

confidence: 55%

Leaky Transcription of Variant Surface Glycoprotein Gene Expression Sites in Bloodstream African Trypanosomes

Alarcon

Pedram²,

Donelson³

1999

Journal of Biological Chemistry

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Trypanosoma brucei undergoes antigenic variation by periodically switching the expression of its variant surface glycoprotein (VSG) genes (vsg) among an estimated 20 -40 telomere-linked expression sites (ES), only one of which is fully active at a given time. We found that in bloodstream trypanosomes one ES is transcribed at a high level and other ESs are expressed at low levels, resulting in organisms containing one abundant VSG mRNA and several rare VSG RNAs. Some of the rare VSG mRNAs come from monocistronic ESs in which the promoters are situated about 2 kilobases upstream of the vsg, in contrast to the polycistronic ESs in which the promoters are located 45-60 kilobases upstream of the vsg. The monocistronic ES containing the MVAT4 vsg does not include the ES-associated genes (esag) that occur between the promoter and the vsg in polycistronic ESs. However, bloodstream MVAT4 trypanosomes contain the mRNAs for many different ESAGs 6 and 7 (transferrin receptors), suggesting that polycistronic ESs are partially active in this clone. To explain these findings, we propose a model in which both mono-and polycistronic ESs are controlled by a similar mechanism throughout the parasite's life cycle. Certain VSGs are preferentially expressed in metacyclic versus bloodstream stages as a result of differences in ESAG expression and the proximity of the promoters to the vsg and telomere.African trypanosomes are protozoan parasites that evade the immune response of their mammalian hosts by periodically switching the major protein on their surface, the variant surface glycoprotein (VSG) 1 (for recent reviews, see Refs. 1-5). Individual VSG genes (vsg) are transcribed from 20 -40 expression sites (ES), each of which is located near a chromosome telomere. The vsgs are maneuvered into the telomere-linked ESs by duplicative translocation or telomere exchange (6, 7). The switch involves either the arrival of a newly duplicated vsg in an active ES (gene conversion) or the activation of another ES already containing a vsg (in situ activation).During their transmission between the tsetse fly vector and a mammalian host, African trypanosomes undergo a series of transformations and pre-adaptive changes (8, 9). The VSG is first expressed at the metacyclic stage in the salivary glands of the tsetse fly as a pre-adaptive measure for entering an unknown host and initiating an infection. The metacyclic trypanosomes are a heterogeneous population expressing a small subset (15 to 20) of the vsg repertoire called the metacyclic variant antigen type (MVAT) vsgs (10, 11). After trypanosomes enter the bloodstream of their host, they continue to express the MVAT vsgs for up to 7 days and then switch to expression of a non-MVAT vsg (12). Occasionally, the MVAT vsgs are re-expressed in the bloodstream stage late in infection (reviewed in Ref. 13).A typical bloodstream ES is composed of a 45-60 kb polycistronic transcription unit that, in addition to the telomerelinked vsg, contains a minimum of eight ES-associated genes (esag). In contrast, the M...

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“…6). This comparison also indicates a region of hypervariability at amino acid positions 151-169, an observation also noted by Borst et al (47) for other ESAG 6 and 7 amino acid sequences.…”

Section: ␣-Amanitin Since In Other Experiments It Repeatedly Was Unafsupporting

confidence: 55%

Leaky Transcription of Variant Surface Glycoprotein Gene Expression Sites in Bloodstream African Trypanosomes

Alarcon

Pedram²,

Donelson³

1999

Journal of Biological Chemistry

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“…Black lines indicate the position of the slots. Lanes: 1, bloodstream form T. brucei; 2, procyclic (insect form) T. brucei; 3-6, human blood, sperm, breast tumor, and ovarian tumor; 7-8, mouse testis and lung; 9, calf thymus; 10-11, human cell lines HeLa and G401; 12-14, human DNAs enriched Ϸ100-fold for telomeric repeats; 12 (Fig. 4) or other kinetoplastids (not shown).…”

Section: Resultsmentioning

confidence: 99%

“…Because we have obtained indirect evidence for T. brucei that HOMeUra is a precursor of J (ref. 12 and unpublished results), these organisms should be candidates for having glucosylated HOMeUra (J).…”

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confidence: 89%

β- d -Glucosyl-hydroxymethyluracil is a conserved DNA modification in kinetoplastid protozoans and is abundant in their telomeres

Leeuwen¹,

Taylor²,

Mondragon³

et al. 1998

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

120

132

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A BSTR ACTThe unusual DNA base ␤-D-glucosylhydroxymethyluracil, called ''J,'' replaces Ϸ0.5-1% of Thy in DNA of African trypanosomes but has not been found in other organisms thus far. In Trypanosoma brucei, J is located predominantly in repetitive DNA, and its presence correlates with the silencing of telomeric genes. Using antibodies specific for J, we have developed sensitive assays to screen for J in a range of organisms and have found that J is not limited to trypanosomes that undergo antigenic variation but is conserved among Kinetoplastida. In all kinetoplastids tested, including the human pathogens Leishmania donovani and Trypanosoma cruzi, J was found to be abundantly present in the (GGGTTA) n telomere repeats. Outside Kinetoplastida, J was found only in Diplonema, a small phagotrophic marine f lagellate, in which we also identified 5-MeCyt. Fractionation of Diplonema DNA showed that the two modifications are present in a common genome compartment, which suggests that they may have a similar function. Dinof lagellates appear to contain small amounts of modified bases that may be analogs of J. The evolutionary conservation of J in kinetoplastid protozoans suggests that it has a general function, repression of transcription or recombination, or a combination of both. T. brucei may have recruited J for the control of genes involved in antigenic variation.In the nuclear DNA of Trypanosoma brucei, Ϸ0.5-1% of Thy is replaced by the modified base ␤-D-glucosyl-hydroxymethyluracil (␤-gluc-HOMeUra) (1). This base that we call ''J'' was detected initially by 32 P-nucleotide postlabeling combined with twodimensional TLC (2D-TLC) (2), and we used this technique to show that approximately one-half of the cellular J is present in both strands of the telomeric (GGGTTA) n repeats (3). To map the location of J more precisely, we have generated antisera that immunoprecipitate J-containing duplex DNA and that detect this DNA with high sensitivity and specificity on dot blots (4). We have used these antisera to demonstrate that J is present in other repetitive DNA sequences but not in housekeeping genes or transcribed repeats (4). Moreover, we have shown that J is responsible for the blocked restriction sites that are present in silent telomeric variant surface glycoprotein (VSG) genes but not in actively transcribed VSG genes (4-6). This result has linked J to the transcriptional control of VSG genes.Thus far, J has been detected only in African trypanosome species that undergo antigenic variation (2). The availability of antibodies acting against J has prompted us to reinvestigate whether J is also present in other organisms. With anti-J-DNA immunoblots, approximately one J per 10 7 bases can be detected, which is Ϸ1,000-fold more sensitive than MATERIALS AND METHODSCells and DNA Analysis. DNA was derived from: T. brucei brucei (427); Trypanosoma congolense (WG81 and TSW13 bloodstream forms and WG81 procyclics); Trypanosoma vivax (Y58); Crithidia fasciculata (ϭ C. luciliae); Leishmania donovani (HU3); Leishmania tarentol...

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“…This stands in contrast to many other parasitic protozoa, such as the African trypanosomes, where antigenic variation of the variant surface glycoprotein (VSG) may occur through several mechanisms. Among these, the most common involve gene conversion‐like mechanisms resulting in the replacement of a complete, expression site‐linked VSG gene, or of gene segments, with formation of mosaic genes (Roth et al ., 1989; Kamper and Barbet, 1992; reviewed in Borst et al ., 1993; Borst and Ulbert, 2001).…”

Section: Introductionmentioning

confidence: 99%

Antigenic variation in Babesia bovis occurs through segmental gene conversion of the ves multigene family, within a bidirectional locus of active transcription

Al-Khedery

Allred

2005

Molecular Microbiology

129

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SummaryAntigenic variation in Babesia bovis is one aspect of a multifunctional virulence/survival mechanism mediated by the heterodimeric variant erythrocyte surface antigen 1 (VESA1) protein that also involves endothelial cytoadhesion with sequestration of mature parasitized erythrocytes. The ves 1 α α α α gene encoding the VESA1a subunit was previously identified. In this study, we present the unique organization of the genomic locus from which ves 1 α α α α is transcribed, and identify a novel branch of the ves multigene family, ves 1 β β β β . These genes are found together, closely juxtaposed and divergently oriented, at the locus of active transcription. We provide compelling evidence that variation of both transcriptionally active genes occurs through a mechanism of segmental gene conversion involving sequence donor genes of similar organization. These results also suggest the possibility of epigenetic regulation through in situ switching among gene loci, further expanding the potential repertoire of variant proteins.

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Control of Antigenic Variation in African Trypanosomas

Cited by 29 publications

References 0 publications

Leaky Transcription of Variant Surface Glycoprotein Gene Expression Sites in Bloodstream African Trypanosomes

Leaky Transcription of Variant Surface Glycoprotein Gene Expression Sites in Bloodstream African Trypanosomes

β- d -Glucosyl-hydroxymethyluracil is a conserved DNA modification in kinetoplastid protozoans and is abundant in their telomeres

Antigenic variation in Babesia bovis occurs through segmental gene conversion of the ves multigene family, within a bidirectional locus of active transcription

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