Chapter 21 : Molecular Aspects of Antigenic Variation in

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Antigenic variation is a key survival strategy employed by a wide range of infectious organisms, allowing them to colonize and persist in a vertebrate host in the face of an evolving immune response. Variant surface antigens (VSA) of the parasite responsible for the most severe form of human malaria, , also contribute significantly to the pathology of disease. Characterization of gene coding sequences is difficult due to their extreme diversity, but there are certain key conserved features in gene structure. The conservation in upstream sequences, in terms of both sequence and organization, may indicate some evolutionary pressure that restricts recombination between limited subsets of genes. The adhesion of different Duffy-binding-like (DBL) and cysteine-rich interdomain region (CIDR) domain types to host cell-surface molecules has been investigated in heterologous expression studies, establishing domains responsible for particular adhesive phenotypes and pinpointing regions critical for binding. Clonal switching of gene expression during chronic infection reflects the sum of several molecular processes, including temporal regulation of gene expression during intraerythrocytic development, mutually exclusive expression of only one variant per infected erythrocytes (IE), and the ability to switch expression in progeny parasites. Chronic infection with malaria is characterized by periodic peaks of parasitemia. A consensus model for variant expression during chronic infections can now be proposed. Following merozoite release from the liver, an initial erythrocyte membrane protein 1 (PfEMP1) variant dominates the first cycle of intraerythrocytic infection.

Citation: Horrocks P, Kyes S, Bull P, Deitsch K. 2005. Molecular Aspects of Antigenic Variation in , p 399-415. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch21

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(A) Chromosomal distribution and orientation of the multigene family. genes are indicated as block arrows with the upstream sequence type () indicated using letters A, B, and C. The most common subtelomeric organization of genes is an gene in tail-to-tail orientation with a gene immediately adjacent to the telomere-associated repeat sequences (TARES). Additional features which may or may not be present are shown in brackets. Some subtelomeric regions contain an gene and/or other members of the () and () multigene families. D and genes are always in the same relative location and/or orientation as -type genes. When present, chromosome-central gene variants are either or type and are typically clustered in a head-to-tail orientation. The CD36-binding phenotype of the encoded PfEMP1 appears to be predictable from gene location, as demonstrated in heterologous protein expression studies ( ). CSA binding is likely to be mediated by the -type -encoded PfEMP1 ( ). genes encoding PfEMP1 for other severe disease phenotypes, such as ICAM-1 binding and CR1-mediated rosetting, have been confirmed with isolate IT/FCR3 but not with the genome project isolate 3D7. These genes are type , (ICAM-1) ( ) and (CR1) ( ). (B) gene structure and sequence features. The basic coding sequence units of a gene include an N-terminal sequence (NTS), at least two DBL domains, and the transmembrane (TM) region with exon 2 encoding the semiconserved acidic terminal sequence (ATS). Noncoding features include the relatively conserved 5′ region (), the intron, and the 3′ region (). A common polymorphic gene is depicted, indicating the formation of the NTS, first DBLα and then CIDR, into what is termed the head structure. The presence of CIDR1α in the head structure predicts that the encoded PfEMP1 binds to CD36. Other domains that may be present in the PfEMP1 molecule are indicated below the basic PfEMP1 organization. Adhesion by these domains to certain host ligands, e.g., DBL1α1 to CR1, DBLβC2 to ICAM-1, and DBLγ to CSA ( ), has been reported, although the presence of these domains in the encoded PfEMP1 molecule should not always be assumed to indicate a particular adhesive property of the IE.

Citation: Horrocks P, Kyes S, Bull P, Deitsch K. 2005. Molecular Aspects of Antigenic Variation in , p 399-415. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch21
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Control of gene expression. The control of gene expression is complex and includes temporal regulation during a cell cycle, mutually exclusive expression of a single variant in an IE, as well as switching of variants expressed in progeny clones. The status of expression for 5 of the 60 genes present per haploid genome is represented in the ring and pigmented trophozoite stages during two cell cycles. Changes to the IE surface are indicated schematically, from smooth (rings) to patterned (pigmented trophozoites), emphasizing that PfEMP1 absent from the IE surface for most of the ring stage is present during trophozoite stages. In the first cell cycle, variant 1 encodes a PfEMP1 variant (light grey dots) on the trophozoite surface, whereas in the second cycle a switch to a variant (dark grey dots) encoded by variant 2 has occurred. During the ring stage of cell cycle 1, variant 1 is exclusively transcribed, giving rise to the corresponding PfEMP1 variant on the trophozoite IE surface while the remainder of the repertoire is transcriptionally silent (at least in terms of mRNA that encodes surface exposed PfEMP1). In trophozoite stage IE, all gene variants are silenced (note transcription from the intronic promoter, although possibly not from that of variant 1) except for one variant (here variant 60, analogous to the conserved ).Thus genes are subject to both temporal and mutually exclusive transcriptional regulation within a cell cycle. During an infection a small proportion of the parasite population may switch expression of PfEMP1. This is represented here by a switch to expression of the PfEMP1 variant 2 in cell cycle 2. variant 2 is subject to the same temporal and mutually exclusive transcriptional regulation as variant 1 during cell cycle 1.

Citation: Horrocks P, Kyes S, Bull P, Deitsch K. 2005. Molecular Aspects of Antigenic Variation in , p 399-415. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch21
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Do genes exist in three transcriptional states? One interpretation of switching rates measured in vitro was that each gene is capable of existing in one of three transcriptional states. First, the on state is where a gene is transcribed and encodes the PfEMP1 molecule on the IE surface. Second, the gene is transcriptionally silent, off but capable of being activated. Transition rates between these two transcriptional states (solid arrows) have been measured and shown to be an intrinsic property of each gene variant. A third transcriptional state was suggested from in vitro data, indicating that the variant expression history impacts on the ability of a gene variant to be switched on. This is termed the heavily silenced transcriptional state. How genes transition to and from this state, and the rates at which this occurs, is not known (broken arrows); their speculative nature is emphasized here by their separation in a second (lower) grey box. Thus, it is proposed that the overall transcriptional status of a gene variant is dependent not only on the intrinsic switch rate between on and off states, but also on whether the gene exists in the heavily silenced state.

Citation: Horrocks P, Kyes S, Bull P, Deitsch K. 2005. Molecular Aspects of Antigenic Variation in , p 399-415. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch21
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Generic image for table

promoter-type and exon 1 comparison for polymorphic genes in 3D7 genome

Citation: Horrocks P, Kyes S, Bull P, Deitsch K. 2005. Molecular Aspects of Antigenic Variation in , p 399-415. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch21
Generic image for table

promoter-type and exon 1 comparison for polymorphic genes in 3D7 genome, conserved within and between genomes

Citation: Horrocks P, Kyes S, Bull P, Deitsch K. 2005. Molecular Aspects of Antigenic Variation in , p 399-415. In Sherman I (ed), Molecular Approaches to Malaria. ASM Press, Washington, DC. doi: 10.1128/9781555817558.ch21

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