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Antigenic Variation in Bacterial Pathogens

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  • Authors: Guy H. Palmer1, Troy Bankhead2, H. Steven Seifert3
  • Editors: Indira T. Kudva4, Qijing Zhang5
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Veterinary Microbiology and Pathology, Paul G. Allen School for Global Animal Health, Washington State University, Pullman, WA 99164; 2: Department of Veterinary Microbiology and Pathology, Paul G. Allen School for Global Animal Health, Washington State University, Pullman, WA 99164; 3: Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611; 4: National Animal Disease Center, Agricultural Research Service, U.S. Department of Agriculture, Ames, IA; 5: Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA
  • Source: microbiolspec January 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.VMBF-0005-2015
  • Received 17 January 2015 Accepted 29 April 2015 Published 29 January 2016
  • Guy H. Palmer, gpalmer@wsu.edu
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  • Abstract:

    Antigenic variation is a strategy used by a broad diversity of microbial pathogens to persist within the mammalian host. Whereas viruses make use of a minimal proofreading capacity combined with large amounts of progeny to use random mutation for variant generation, antigenically variant bacteria have evolved mechanisms which use a stable genome, which aids in protecting the fitness of the progeny. Here, three well-characterized and highly antigenically variant bacterial pathogens are discussed: , and . These three pathogens display a variety of mechanisms used to create the structural and antigenic variation needed for immune escape and long-term persistence. Intrahost antigenic variation is the focus; however, the role of these immune escape mechanisms at the population level is also presented.

  • Citation: Palmer G, Bankhead T, Seifert H. 2016. Antigenic Variation in Bacterial Pathogens. Microbiol Spectrum 4(1):VMBF-0005-2015. doi:10.1128/microbiolspec.VMBF-0005-2015.

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/content/journal/microbiolspec/10.1128/microbiolspec.VMBF-0005-2015
2016-01-29
2017-09-21

Abstract:

Antigenic variation is a strategy used by a broad diversity of microbial pathogens to persist within the mammalian host. Whereas viruses make use of a minimal proofreading capacity combined with large amounts of progeny to use random mutation for variant generation, antigenically variant bacteria have evolved mechanisms which use a stable genome, which aids in protecting the fitness of the progeny. Here, three well-characterized and highly antigenically variant bacterial pathogens are discussed: , and . These three pathogens display a variety of mechanisms used to create the structural and antigenic variation needed for immune escape and long-term persistence. Intrahost antigenic variation is the focus; however, the role of these immune escape mechanisms at the population level is also presented.

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Image of FIGURE 1
FIGURE 1

Emergence of Msp2 antigenic variants during cyclic bacteremia. replicates to >10 organisms per ml during acute infection; the immune response does not completely clear the infection, which persists in a series of sequential bacteremia peaks. Organisms in each peak express an antigenically variant immunodominant surface protein, Msp2, which is not recognized by existing antibody at the time of emergence (as illustrated by the IgG immunoblot for the peak 2 variant). Immune recognition of the variant results in clearance followed by emergence of novel variants in peak 3. Original data from references 14 and 27 .

Source: microbiolspec January 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.VMBF-0005-2015
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Image of FIGURE 2
FIGURE 2

Generation of Msp2 variants through gene conversion. () Genomic structure of the donor and expression site loci. The 1.2-Mb genome is a single circular chromosome and encodes a single Msp2 expression site (ES). Multiple donor alleles, silent in their chromosomal loci, encode unique hypervariable regions (HVRs), which are expressed only when recombined into the expression site. The allelic repertoire shown is for the St. Maries strain; alleles encoding a unique HVR are shown in different colors; duplicated alleles (2, 3H1; 1, 9H1) are shown in the same color. The expression site variant, in this example, corresponds to that encoded by the full 9H1 (or 1) allele. () Gene conversion generates unique expression site variants. Sequential rounds of recombination result in replacement of the existing expression site copy by either a whole allelic donor sequence (as shown in the first gene conversion event in which allele 2 is the donor) or progressive modification of the existing expression site copy by segmental gene conversion. Over time, this process of segmental gene conversion generates complex expression site mosaics derived from multiple allelic donors and is reflected in a complexity score. The light blue regions flanking the expression site represent the conserved 5′ and 3′ domains; identical, truncated domains flank each donor allele and direct recombination. Figure and legend are from reference 41 with permission.

Source: microbiolspec January 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.VMBF-0005-2015
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Image of FIGURE 3a
FIGURE 3a

Complex variants are favored only under selection pressure of the adaptive immune response. () Development of complex Msp2 variants during persistent infection; complexity, measured by the number of expression site segments derived from different donor alleles (see Fig. 2B ) is plotted on the axis, and duration of infection (in months) is shown on the axis. At 24 months of infection (solid bar), this animal was used as the source for direct transmission by intravenous inoculation of into immunologically naïve animals () or for acquisition feeding of for tick transmission (, ). () Expression of simple Msp2 variants following direct inoculation of complex variants into an immunologically naïve animal. Solid bar, complexity score of variants in persistently infected calf 983. These were inoculated intravenously into immunologically naïve calf 1125. Open bars, complexity of the Msp2 variants emergent during the 3 weeks of acute bacteremia. () Expression of simple Msp2 variants in the tick salivary gland. Solid bar, complexity score of Msp2 variants in persistently infected calf 983 during the acquisition feeding of ticks. Open bars, complexity of the variants in the salivary glands of ticks subsequently transmission-fed on each of four calves (calves 1104, 1113, 1118, and 1121). () Expression of simple Msp2 variants following tick transmission to immunologically naïve animals. Solid bar, complexity score of variants in persistently infected calf 983 during the acquisition-feeding of ticks. Open bars, complexity of the variants arising during acute infection following tick transmission to each of four immunologically naïve calves (1104, 1113, 1118, and 1121). Data, figure, and legend from reference 41 with permission.

Source: microbiolspec January 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.VMBF-0005-2015
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Image of FIGURE 3b
FIGURE 3b

Complex variants are favored only under selection pressure of the adaptive immune response. () Development of complex Msp2 variants during persistent infection; complexity, measured by the number of expression site segments derived from different donor alleles (see Fig. 2B ) is plotted on the axis, and duration of infection (in months) is shown on the axis. At 24 months of infection (solid bar), this animal was used as the source for direct transmission by intravenous inoculation of into immunologically naïve animals () or for acquisition feeding of for tick transmission (, ). () Expression of simple Msp2 variants following direct inoculation of complex variants into an immunologically naïve animal. Solid bar, complexity score of variants in persistently infected calf 983. These were inoculated intravenously into immunologically naïve calf 1125. Open bars, complexity of the Msp2 variants emergent during the 3 weeks of acute bacteremia. () Expression of simple Msp2 variants in the tick salivary gland. Solid bar, complexity score of Msp2 variants in persistently infected calf 983 during the acquisition feeding of ticks. Open bars, complexity of the variants in the salivary glands of ticks subsequently transmission-fed on each of four calves (calves 1104, 1113, 1118, and 1121). () Expression of simple Msp2 variants following tick transmission to immunologically naïve animals. Solid bar, complexity score of variants in persistently infected calf 983 during the acquisition-feeding of ticks. Open bars, complexity of the variants arising during acute infection following tick transmission to each of four immunologically naïve calves (1104, 1113, 1118, and 1121). Data, figure, and legend from reference 41 with permission.

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Image of FIGURE 3c
FIGURE 3c

Complex variants are favored only under selection pressure of the adaptive immune response. () Development of complex Msp2 variants during persistent infection; complexity, measured by the number of expression site segments derived from different donor alleles (see Fig. 2B ) is plotted on the axis, and duration of infection (in months) is shown on the axis. At 24 months of infection (solid bar), this animal was used as the source for direct transmission by intravenous inoculation of into immunologically naïve animals () or for acquisition feeding of for tick transmission (, ). () Expression of simple Msp2 variants following direct inoculation of complex variants into an immunologically naïve animal. Solid bar, complexity score of variants in persistently infected calf 983. These were inoculated intravenously into immunologically naïve calf 1125. Open bars, complexity of the Msp2 variants emergent during the 3 weeks of acute bacteremia. () Expression of simple Msp2 variants in the tick salivary gland. Solid bar, complexity score of Msp2 variants in persistently infected calf 983 during the acquisition feeding of ticks. Open bars, complexity of the variants in the salivary glands of ticks subsequently transmission-fed on each of four calves (calves 1104, 1113, 1118, and 1121). () Expression of simple Msp2 variants following tick transmission to immunologically naïve animals. Solid bar, complexity score of variants in persistently infected calf 983 during the acquisition-feeding of ticks. Open bars, complexity of the variants arising during acute infection following tick transmission to each of four immunologically naïve calves (1104, 1113, 1118, and 1121). Data, figure, and legend from reference 41 with permission.

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Image of FIGURE 3d
FIGURE 3d

Complex variants are favored only under selection pressure of the adaptive immune response. () Development of complex Msp2 variants during persistent infection; complexity, measured by the number of expression site segments derived from different donor alleles (see Fig. 2B ) is plotted on the axis, and duration of infection (in months) is shown on the axis. At 24 months of infection (solid bar), this animal was used as the source for direct transmission by intravenous inoculation of into immunologically naïve animals () or for acquisition feeding of for tick transmission (, ). () Expression of simple Msp2 variants following direct inoculation of complex variants into an immunologically naïve animal. Solid bar, complexity score of variants in persistently infected calf 983. These were inoculated intravenously into immunologically naïve calf 1125. Open bars, complexity of the Msp2 variants emergent during the 3 weeks of acute bacteremia. () Expression of simple Msp2 variants in the tick salivary gland. Solid bar, complexity score of Msp2 variants in persistently infected calf 983 during the acquisition feeding of ticks. Open bars, complexity of the variants in the salivary glands of ticks subsequently transmission-fed on each of four calves (calves 1104, 1113, 1118, and 1121). () Expression of simple Msp2 variants following tick transmission to immunologically naïve animals. Solid bar, complexity score of variants in persistently infected calf 983 during the acquisition-feeding of ticks. Open bars, complexity of the variants arising during acute infection following tick transmission to each of four immunologically naïve calves (1104, 1113, 1118, and 1121). Data, figure, and legend from reference 41 with permission.

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Image of FIGURE 4
FIGURE 4

strain superinfection is favored under the selective pressure of high population immunity. Circles indicate the existing animal population at T: white represents uninfected and immunologically naïve hosts; blue represents hosts carrying strain A; orange represents strain B; and purple represents hosts superinfected with strains A and B. Squares represent individual hosts introduced to the population by birth or immigration. The intrinsic transmission fitness is greater for strain A than strain B (TE ≫ TE). Under conditions of low prevalence of infection (and hence low population immunity), strain A predominates. Following introduction of strain B, its transmission is at a strong disadvantage and there is minimal selective pressure for strain B superinfection. Consequently, strain A predominance is maintained over time. Under conditions of high prevalence of infection (and high population immunity), strain A is predominant, but there is strong selective pressure for strain B superinfection. Strain A transmission is favored for newly introduced naïve hosts and thus remains predominant but accompanied by prevalent superinfection. Figure and legend from reference 54 with permission.

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Image of FIGURE 5
FIGURE 5

The locus of B31. The illustration shows the arrangement of the expression site, , and the contiguous array of 15 silent cassettes comprising the locus on the right telomeric end of lp28-1. The six variable regions of the central cassette are colored light blue, while the six invariant regions are colored dark blue. The black bars flanking the cassette region and silent cassettes represent the 17-bp direct repeats. The silent cassettes ( to ) are not drawn to scale. Arrows positioned at the beginning of and silent cassettes indicate the respective orientations. The arrows located within the intergenic region denote the inverted DNA repeat. DR, 17-bp direct repeat; , promoter. Figure adapted from reference 191 with permission.

Source: microbiolspec January 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.VMBF-0005-2015
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FIGURE 6

Telomere-mediated deletion of the locus in . () Construction strategy for the generation of the deletion mutant clone of B31. The target sequence for insertion (green) is chosen so that only the locus would be deleted from the lp28-1 plasmid. The genes encoding plasmid maintenance proteins that have been previously shown to allow autonomous replication are shown as black arrows. () Schematic of the construction strategy for the lp28-1Δ plasmid. The target sequence for insertion (green) was chosen so that only the genes encoding proteins that allow autonomous replication of lp28-1 (shown as arrows arranged from left to right) and the right side of lp28-1 would remain. Hairpin telomeres are shown as red hatched regions. Figure adapted from reference 78 with permission.

Source: microbiolspec January 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.VMBF-0005-2015
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FIGURE 7

Overview of antigenic switching in . Variant-specific segments act as a source of DNA for nonreciprocal recombination events with the expression locus. Through this process, segments of the variable region (blue) are replaced by sections of varied length and location from the donor sequences. In the example shown, three sequential gene conversion events (represented by dashed lines) occur within each expression site through recombination with the colored donor sections (yellow, green, or red) to generate a new expression site sequence with a mosaic structure. Figure adapted from reference 4 with permission.

Source: microbiolspec January 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.VMBF-0005-2015
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FIGURE 8

Model for VlsE-mediated protection of surface antigens. () Shortly after host infection, upregulation of expression leads to surface localization of the encoded lipoprotein. Interaction of VlsE with other proteins results in a complex that functions to shield epitopes of these surface antigens. Continued gene conversion leading to production of VlsE variants is necessary to avoid killing by antibodies raised against the parental and subsequent VlsE variants, allowing for sustained epitope masking. Absence () or low expression () of VlsE allows binding of neutralizing antibodies to surface antigens that ultimately leads to spirochete death (denoted by a large red X). A legend indicating the identity of the various molecular cartoon depictions is provided at the bottom of the figure.

Source: microbiolspec January 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.VMBF-0005-2015
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FIGURE 9

Polynucleotide repeat (PNR)–based phase variation in . () PNR within a promoter of your favorite gene (). The yellow double-headed arrow represents the promoter with a -35 and -10 sequence and a PNR in between these promoter elements. The blue circle shows a ribosome binding site to initiate translation. (i) When the PNR repeat number is in the optimal spacing, the promoter initiates maximal transcription as long as other regulatory signals do not prevent expression. (ii) When the PNR changes ±1 nucleotide, the spacing between the -35 and -10 elements is not optimal, but there is still transcriptional initiation to produce a low level of gene expression. (iii) When the PNR number increases or decreases due to a spacing that does not allow RNA polymerase to effectively interact with the promoter, there is essentially no transcription. () PNR within a coding sequence. (i) The PNR length maintains the reading frame to translate the entire gene product. (ii) Change in the PNR length by ±1 or 2 changes the reading frame downstream of the PNR and usually terminates translation prematurely. It is possible that this change in reading frame could result in a different protein product.

Source: microbiolspec January 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.VMBF-0005-2015
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FIGURE 10

Lipooligosaccharide (LOS) and opacity (Opa) protein phase variation. () LOS variation. Shown is one of the variable LOS biosynthetic gene clusters. (i) The glycosyltransferase gene has a guanine polynucleotide repeat (PNR) within the coding sequence that can change the repeat number ±1. (ii) Sugar residues added by each transglycosylase. (iii) When the PNR is in the correct reading frame, the glycosyltransferase is produced to add a galactose residue to the acceptor glucose. This galactose is then a substrate for the LgtB glycosyltransferase to add a glucose, which is then a substrate for the sialyltransferase (Lst). (iv) When the PNR changes number and causes a frame shift, this form of the LOS cannot be modified or sialylated. () Opa variation. (i) A representative gene showing the pentamer repeat within the signal sequence (SS). (ii) Phase-ON: when the pentamer repeat number encodes an in-frame protein, the full protein is translated and the signal sequence is cleaved during secretion. (iii) Phase-OFF: when the pentamer repeat number changes to be out of frame and an altered protein coding sequence is produced (blue), leading to a premature stop codon.

Source: microbiolspec January 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.VMBF-0005-2015
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FIGURE 11

pilin antigenic variation. () The pilin loci. (i) The pilin expression locus () has a promoter sequence to initiate transcription; a seven-amino-acid signal sequence (SS, green), an absolutely conserved, N-terminal constant coding sequence (N-term, purple), and a variable carboxy-terminal coding sequence (C-term, red). The G4-forming sequence is represented by the blue star, and the sRNA transcript is represented by the thin arrow. (ii) A variant gene copy that has variant pilin C-terminal coding sequences (C-term, orange) but cannot express a protein product. This copy has a frame shift in the 5′-coding sequences (X). Each locus can have one to six repeated copies ( = 1 to 6). () Pilin variation. Nonreciprocal transfer of variant copy sequences into the locus produces pilin variants. The sequences that are transferred can be from any part of the copy that overlaps with the sequence as long as there are regions of microhomology at the ends of the transferred sequence (not shown). Some (but not all) copies encode a frame shift in their 5′ potential coding sequences that can result in an altered reading frame (blue), a premature stop codon, and a nonpiliated variant. () The G4-forming sequence and promoter for the -acting sRNA. The sequence shown is on the bottom strand of the cartoons in parts A and B. The sRNA promoter is indicated by the boxed -10 and -35 sequences. The sRNA required for pilin antigenic variation initiates (+1 sRNA) within the second set of guanines in the G4 forming sequence.

Source: microbiolspec January 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.VMBF-0005-2015
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