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Chapter 12 : Persistence and Antigenic Variation

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Abstract:

This chapter focuses on the genera and . Typically, antigenically variable proteins are immunodominant and thus allow evasion of the predominant immune responses. The donor allele repertoire remains unchanged during antigenic variation, while the expression-site variant is lost. This method is employed by some rickettsiae in the family and allows for lifelong persistence in the host with donor allele repertoires 10- to 100-fold smaller than those found in African trypanosomes. Earlier work has demonstrated that major surface proteins (MSP)2 and MSP3 are immunodominant, antigenically variable proteins that are instrumental in evading the host immune response. , a small ruminant pathogen, has been shown to establish persistent infections in goats. Antigenic variation in is effected through the homolog of . The antibody response to the MSP2 HVR is variant specific and diminishes rapidly, consistent with the idea that antigenic variation of MSP2 is responsible for persistence. Research shows that the implications of donor allele repertoires go beyond antigenic variation in the individual hosts, and that they also play critical roles in the epidemiology of pathogen strain structure and possibly host tropism.

Citation: Brayton K. 2012. Persistence and Antigenic Variation, p 366-390. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch12

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Image of FIGURE 1
FIGURE 1

Infection scenarios. Upon infection, pathogen load can increase in an uncontrolled fashion, ultimately causing death (solid line). Alternatively, a controlling immune response can be established, resulting in clearance of the pathogen and resolution of disease (dashed line). Finally, in the face of an adaptive immune response, the pathogen is able to evade recognition and enter a persistent phase of infection (dotted line). In persistence mediated by antigenic variation, the infection scenario is typically characterized by waves of parasitemia, reflecting control of variants, followed by emergence of new variants that are not immediately recognized by the existing immune response. doi:10.1128/9781555817336.ch12.f1

Citation: Brayton K. 2012. Persistence and Antigenic Variation, p 366-390. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch12
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Image of FIGURE 2
FIGURE 2

Paradigms of antigenic variation. Antigenic shift is the result of a recombination event; in bacteria it can result either from a classical homologous recombination event, wherein the donor allele (DA) is exchanged with the expressed copy of the gene (ES), resulting in a change in the donor allele repertoire, or from a specialized type of homologous recombination called gene conversion where the donor allele is “copied and pasted” into the expression site, thus maintaining the donor allele repertoire. Antigenic variation sensu stricto is a rapid process that requires one or more expression sites and a pool of donor alleles. Antigenic variability is the accumulation of mutations in the expression-site copy of a gene over time, typically a slower process. doi:10.1128/9781555817336.ch12.f2

Citation: Brayton K. 2012. Persistence and Antigenic Variation, p 366-390. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch12
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Image of FIGURE 3
FIGURE 3

and expression sites (ES), genomic arrangement, and donor allele repertoires. (A) The (left) and (right) operons that are the sole expression sites for these genes. The promoter for each operon is indicated by the bent arrowhead. is transcribed from an operon of four genes with at the 3′ end. The other genes in the operon ( to -) are members of PF01617, as is the gene immediately upstream (), and these are depicted in green. A putative transcriptional regulator () that has been used as an indicator of synteny resides upstream and is shown in red. The operon contains three genes with at the 3′ end. The other two genes in the operon were annotated as and - (red), and recently have been implicated as being homologs of , a component of the type IV secretion system. , 3′ to the operon, has been used to identify the syntenic locus in related organisms, and is shown in red. (B) The genomic arrangement of the and expression sites and donor allele repertoires. Alleles depicted in identical colors (e.g., 3H1 and 2) have identical HVR sequences. The genome backbone is shown as gray. (C) The donor allele and pseudogene repertoires for and , showing the relative portion of the expression-site molecule that each encodes. The remnant sequences (R1 and R2) do not contain any portion of the HVR and could not serve as donor alleles. has a 3′ end identical to (solid blue), regions flanking the HVR that have similarity to (diagonal stripes), and a unique 5′ end (stippled). doi:10.1128/9781555817336.ch12.f3

Citation: Brayton K. 2012. Persistence and Antigenic Variation, p 366-390. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch12
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Image of FIGURE 4
FIGURE 4

The anchoring model for gene conversion. A segment of the genome containing the expression site (ES) and several donor alleles is shown (not to scale). The first recombination event illustrates the complete HVR from donor allele 2 being recombined into the expression site, with both recombination sites occurring in the conserved flanking regions. The donor allele repertoire remains unchanged. The second recombination event incorporates a segment of donor allele G11 into the expression site. Importantly, one recombination event has occurred in the 5′ conserved flanking region, while the other has occurred in the HVR without the requirement for sequence identity at the recombination site. In the anchoring model, one end of the newly recombined segment will always be juxtaposed to the conserved flanking regions, as the sequence identity in these regions anchors the recombination complex. doi:10.1128/9781555817336.ch12.f4

Citation: Brayton K. 2012. Persistence and Antigenic Variation, p 366-390. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch12
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Image of FIGURE 5
FIGURE 5

Schematic representation of subsp. and expression sites (ES), genomic arrangement, and donor allele repertoires. (A) The (left) and (right) operons that are the sole expression sites for these genes. is the 3′ gene in an operon with to . The putative and genes reside upstream and are depicted in red and green, respectively. The candidate expression site is flanked by and (red). (B) The genomic arrangement of the and expression site and donor allele repertoires. Alleles depicted in identical colors (e.g., G1 and G2) have identical HVR sequences. The genome backbone is shown as gray. (C) The donor allele and remnant sequence repertoires for and , showing the relative portion of the expression-site molecule that each encodes. The remnant sequence (R1) does not contain any portion of the HVR. has a 3′ end identical to (solid blue), regions flanking the HVR that have similarity to (diagonal stripes), and a unique 5′ end (stippled) that is shorter than the 5′ end sequence found in . Comparison with Fig. 3 shows that the synteny of these sequences has not been maintained. doi:10.1128/9781555817336.ch12.f5

Citation: Brayton K. 2012. Persistence and Antigenic Variation, p 366-390. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch12
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Image of FIGURE 6
FIGURE 6

Schematic representation of expression site (ES), genomic arrangement, and donor allele/pseudogene repertoire. (A) Genomic arrangement of the operon. is shown in black at the 3′ end of the two-gene operon. A bent arrow indicates the position of the operon promoter. is also known as (Barbet et al., 2003), and this gene and (shown in gray) are both members of PF01617 and therefore related to . The putative transcriptional regulator (, in white) is found upstream from the operon. (B) Genomic arrangement of the family. Sequences with identity to are shown as black bars, with the expression site marked with a longer bar. The genome backbone is gray. (C) Diagram of the gene family, with conserved regions shown as black and the HVR shown as gray. There are 10 full-length genes, 75 sequences that contain the HVR and could act as donor alleles, and 26 pseudogenes that are unlikely to contribute to variation as they are lacking the necessary components for gene conversion events, i.e., conserved flanking regions and HVR. doi:10.1128/9781555817336.ch12.f6

Citation: Brayton K. 2012. Persistence and Antigenic Variation, p 366-390. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch12
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Image of FIGURE 7a
FIGURE 7a

Alignment of deduced amino acid sequences for superfamily genes and . Each sequence is labeled with its genome identifier number (taken from GenBank accession no. CP000235) ( ) and represents an sequence that is full length or nearly full length. The expression site sequence is denoted with “ES.” All genes are annotated as paralogs except APH_1361, which is annotated as . The central HVR is boxed. Conserved residues are highlighted in black, while blocks of similar residues are shown on a gray background. A positionally conserved methionine residue, indicated with an arrow, may be the start codon for these genes. Numbers above the alignment indicate alignment position number, while numbers in parentheses indicate position for each sequence. The sequence used for alignment is from GenBank accession no. U07862 ( ). doi:10.1128/9781555817336.ch12.f7

Citation: Brayton K. 2012. Persistence and Antigenic Variation, p 366-390. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch12
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Image of FIGURE 7b
FIGURE 7b

Alignment of deduced amino acid sequences for superfamily genes and . Each sequence is labeled with its genome identifier number (taken from GenBank accession no. CP000235) ( ) and represents an sequence that is full length or nearly full length. The expression site sequence is denoted with “ES.” All genes are annotated as paralogs except APH_1361, which is annotated as . The central HVR is boxed. Conserved residues are highlighted in black, while blocks of similar residues are shown on a gray background. A positionally conserved methionine residue, indicated with an arrow, may be the start codon for these genes. Numbers above the alignment indicate alignment position number, while numbers in parentheses indicate position for each sequence. The sequence used for alignment is from GenBank accession no. U07862 ( ). doi:10.1128/9781555817336.ch12.f7

Citation: Brayton K. 2012. Persistence and Antigenic Variation, p 366-390. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch12
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Image of FIGURE 8
FIGURE 8

Schematic representation of species homolog tandem gene arrays. Genome sequences were used to identify the genomic context of sequences for (strain Jake; GenBank accession no. CP000107), (strain Arkansas; GenBank accession no. CP000236), and (strain Welgevonden; GenBank accession no. CR767821); however, nomenclature was taken from published analyses of these gene loci, as was information on ( ). The genome backbone is indicated by a gray line; PF01617 genes are shown in black, and other unrelated genes are shown in white. Gene names are indicated or shown as “H” for hypothetical. contains a second smaller locus wherein genes , , and are duplicated. doi:10.1128/9781555817336.ch12.f8

Citation: Brayton K. 2012. Persistence and Antigenic Variation, p 366-390. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch12
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Tables

Generic image for table
TABLE 1

donor allele repertoires

Citation: Brayton K. 2012. Persistence and Antigenic Variation, p 366-390. In Palmer G, Azad A (ed), Intracellular Pathogens II: . ASM Press, Washington, DC. doi: 10.1128/9781555817336.ch12

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