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Chapter 40 : Antigenic Variation in Eukaryotic Parasites

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Abstract:

Organisms with complex genomes cannot afford imprecise genome replication and have to find more sophisticated ways to vary their antigens. This chapter is restricted to antigenic variation in pathogenic protozoa and fungi, and will only describe antigenic variation in four organisms: , , , and . Most of the available evidence suggests, however, that DNA rearrangements are not involved in silencing or in situ switches. This chapter briefly touches on this topic of reversible allelic exclusion between expression sites. The simplicity of the antigenic variation strategy is only apparent, however. The author, limits the discussion to a brief summary of the gene family to allow a comparison with antigenic variation in the other parasites discussed in this chapter. A model showing how reciprocal recombination between the UCS and telomeric MSG genes results in antigenic variation is shown. A complication in the study of Giardia antigenic variation is the polyploidy of its nuclear DNA. The spectacular bacterial pathogens, exemplified by and species, set the tone, and the African trypanosomes appeared to confirm the idea that real antigenic variation requires real DNA rearrangements. DNA rearrangements require enzymes for cutting and joining DNA, and a systematic disruption of the genes for each of these enzymes, as initiated by McCulloch and Barry in trypanosomes, should eventually give us a complete overview of the DNA recombination pathways involved in antigenic variation.

Citation: Borst P. 2002. Antigenic Variation in Eukaryotic Parasites, p 953-971. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch40

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Figures

Image of Figure 1
Figure 1

Life cycle of the African trypanosome, , showing some of the major life cycle stages. The short stumpy trypomastigote form is preadapted to the tsetse fly and does not multiply. The long slender trypomastigote can be grown in serum-based culture media; the procyclic trypomastigote form can be grown in defined simple media. Reprinted from reference 20 with permission.

Citation: Borst P. 2002. Antigenic Variation in Eukaryotic Parasites, p 953-971. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch40
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Image of Figure 2
Figure 2

A schematic representation of the cell surface of bloodstream form of , showing a VSG dimer (15, 23), a Tf receptor molecule ( ), which is only present in the flagellar pocket, and a hexose transporter (THT) molecule ( ). For size comparison, a Tf molecule (upper left) and an immunoglobulin (Ig) G antibody molecule (upper right) are shown. The dimensions of the VSG dimer are based on the crystal structure of the N-terminal domain of the protein ( ). The VSG is attached to the glycosyl phosphatidyl inositol anchor via its C-terminal region; the crystal structure of this region is not yet known. The Tf receptor structure is based on its homology with the VSG dimer ( ) (see text). The hexose transporter structure is not based on any solid structural information but is derived from a hypothetical model ( ) of GLUT1. Modified from reference ( ) and reproduced from reference 20 with permission.

Citation: Borst P. 2002. Antigenic Variation in Eukaryotic Parasites, p 953-971. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch40
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Image of Figure 3
Figure 3

VSG gene expression site of . The standard bloodstream form expression site is modeled after that in reference 85. The flag is the promoter, and the broken line is the primary transcript. ESAGs, expression site-associated genes; rep., repeats. The metacyclic expression site is modeled after that in references 9 and 84. The end of the primary transcript of both expression sites has not been determined and may be further downstream.

Citation: Borst P. 2002. Antigenic Variation in Eukaryotic Parasites, p 953-971. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch40
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Image of Figure 5
Figure 5

Donors and acceptor in the duplicative transposition of VSG genes. The acceptor site is identical to that in Fig. 3 , but the elements important for VSG gene transposition are highlighted and slightly enlarged to make them better visible. The overall size of the expression site from promoter down to the telomere tip may vary in size between about 45 and 65 kb ( ), although exceptional sites may be shorter ( ); the 70-bp imperfect repeats may vary at least between 5 and 20 kb ( ); and the (GGGTTA) repeats may grow to at least 20 kb ( ). See text for further details.

Citation: Borst P. 2002. Antigenic Variation in Eukaryotic Parasites, p 953-971. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch40
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Image of Figure 4
Figure 4

The major mechanisms of VSG switching in . The thick lines represent the so-called 221 VSG expression site, with the flag indicating a promoter, the black box indicating the 221 VSG gene, and the white box indicating a new telomeric VSG gene (VSG gene X). Y and Z are other chromosome-internal VSG genes. The hygromycin resistance gene introduced behind the promoter of the 221 expression site ( Fig. 3 ) is indicated by a hatched box. The dashed line with an arrow indicates the direction of transcription. The figure illustrates how the different mechanisms can be distinguished, by using an expression site marked with a resistance gene. The gene is actively transcribed following the switch in all mechanisms, with the exception of the in situ switch. In gene conversion mechanisms the 221 VSG gene (the only copy of this gene in the genome of the 427 stock of ) is lost. In the reciprocal translocation the 221 VSG gene moves to another chromosome. Reprinted from reference 22 with permission.

Citation: Borst P. 2002. Antigenic Variation in Eukaryotic Parasites, p 953-971. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch40
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Image of Figure 6
Figure 6

Models of the installation of MSG sequences at the expression site of . (A) The structure of a telomeric expression site locus is depicted as in f. sp. . This locus starts with exon I of the UCS (stippled rectangle), followed by an intron (line), exon II (stippled rectangle), the CRJE (hatched rectangle), and the MSG gene (gray rectangle). The expression site locus is presumably structured the same way in f. sp. , the MSG gene at the expression site can be changed by recombination at any of three locations: (i) between two CRJEs; (ii) within MSG open-reading frames; or (iii) between two copies of exon II (in cases in which the donor MSG gene has a copy of exon II). By contrast, donor MSGs in f. sp. lack exon II and, therefore, lack pathway 3. (B) Outcomes of switching. Reprinted from reference 95 with permission.

Citation: Borst P. 2002. Antigenic Variation in Eukaryotic Parasites, p 953-971. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch40
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Tables

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Table 1

Antigenic variation of eukaryotic parasites: mechanisms used to control expression of surface antigen genes

Citation: Borst P. 2002. Antigenic Variation in Eukaryotic Parasites, p 953-971. In Craig N, Craigie R, Gellert M, Lambowitz A (ed), Mobile DNA II. ASM Press, Washington, DC. doi: 10.1128/9781555817954.ch40

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