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Antigenic Variation Systems of Lyme Disease : Eluding Host Immunity through both Random, Segmental Gene Conversion and Framework Heterogeneity

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  • Author: Steven J. Norris1
  • Editors: Martin Gellert2, Nancy Craig3
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Pathology and Laboratory Medicine, UTHealth Medical School, PO Box 20708, Houston, TX 77225-0708; 2: National Institutes of Health, Bethesda, MD; 3: Johns Hopkins University, Baltimore, MD
  • Source: microbiolspec December 2014 vol. 2 no. 6 doi:10.1128/microbiolspec.MDNA3-0038-2014
  • Received 13 July 2014 Accepted 16 July 2014 Published 05 December 2014
  • Steven J. Norris, steven.j.norris@uth.tmc.edu
image of <span class="jp-italic">vls</span> Antigenic Variation Systems of Lyme Disease <span class="jp-italic">Borrelia</span>: Eluding Host Immunity through both Random, Segmental Gene Conversion and Framework Heterogeneity
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  • Abstract:

    Spirochetes that cause Lyme borreliosis (also called Lyme disease) possess the locus, encoding an elaborate antigenic variation system. This locus contains the expression site as well as a contiguous array of silent cassettes, which contain variations of the central cassette region of . The locus is present on one of the many linear plasmids in the organism, e.g. plasmid lp28-1 in the strain B31. Changes in the sequence of occur continuously during mammalian infection and consist of random, segmental, unidirectional recombination events between the silent cassettes and the cassette region of . These gene conversion events do not occur during culture or the tick portion of the infection cycle of or the other related species that cause Lyme disease. The mechanism of recombination is largely unknown, but requires the RuvAB Holliday junction branch migrase. Other features of the locus also appear to be required, including locations of and the silent cassettes and high G+C content and GC skew. The system is required for long-term survival of Lyme in infected mammals and represents an important mechanism of immune evasion. In addition to sequence variation, immune selection also results in significant heterogeneity in the sequence of the surface lipoprotein VlsE. Despite antigenic variation, VlsE generates a robust antibody response, and both full-length VlsE and the C6 peptide (corresponding to invariant region 6) are widely used in immunodiagnostic tests for Lyme disease.

  • Citation: Norris S. 2014. Antigenic Variation Systems of Lyme Disease : Eluding Host Immunity through both Random, Segmental Gene Conversion and Framework Heterogeneity. Microbiol Spectrum 2(6):MDNA3-0038-2014. doi:10.1128/microbiolspec.MDNA3-0038-2014.

Key Concept Ranking

Holliday Junction Resolvase
0.47618404
Ribosome Binding Site
0.43505105
Outer Membrane Proteins
0.4146416
0.47618404

References

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2014-12-05
2017-09-21

Abstract:

Spirochetes that cause Lyme borreliosis (also called Lyme disease) possess the locus, encoding an elaborate antigenic variation system. This locus contains the expression site as well as a contiguous array of silent cassettes, which contain variations of the central cassette region of . The locus is present on one of the many linear plasmids in the organism, e.g. plasmid lp28-1 in the strain B31. Changes in the sequence of occur continuously during mammalian infection and consist of random, segmental, unidirectional recombination events between the silent cassettes and the cassette region of . These gene conversion events do not occur during culture or the tick portion of the infection cycle of or the other related species that cause Lyme disease. The mechanism of recombination is largely unknown, but requires the RuvAB Holliday junction branch migrase. Other features of the locus also appear to be required, including locations of and the silent cassettes and high G+C content and GC skew. The system is required for long-term survival of Lyme in infected mammals and represents an important mechanism of immune evasion. In addition to sequence variation, immune selection also results in significant heterogeneity in the sequence of the surface lipoprotein VlsE. Despite antigenic variation, VlsE generates a robust antibody response, and both full-length VlsE and the C6 peptide (corresponding to invariant region 6) are widely used in immunodiagnostic tests for Lyme disease.

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FIGURE 1

Characteristics of the locus of B31. (A) Arrangement of the expression site and the 15 silent cassettes near the telomere of the linear plasmid lp28-1. The promoter for is indicated by the short arrow and the orientation of the silent cassettes is shown by the large arrow. (B) The cassette regions contain six variable regions (VR1 through VR6) separated by relatively invariant regions. The graph indicates the number of different amino acids encoded by the silent cassettes at each codon in the aligned sequences. (C) Unidirectional, random, segmental recombination occurs sequentially during mammalian infection, as indicated by this hypothetical example of sequential recombination between and silent cassettes 9, 7, and 10. doi:10.1128/microbiolspec.MDNA3-0038-2014.f1

Source: microbiolspec December 2014 vol. 2 no. 6 doi:10.1128/microbiolspec.MDNA3-0038-2014
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FIGURE 2

Dendrogram depicting the conservation and diversity of VlsE amino acid sequences and their relatedness to Vlp proteins from relapsing fever organisms. Representative Vlp proteins from (Bh) strains DAH and HS1 are clustered into two groups at the top of the dendrogram. The B31 strain of (Bb) and closely related European strains form a distinct grouping at the bottom, whereas the remaining Lyme disease VlsE sequences exhibit considerable diversity. Additional species abbreviations: Bg = , Bs = , Ba = , and Bv = . doi:10.1128/microbiolspec.MDNA3-0038-2014.f2

Source: microbiolspec December 2014 vol. 2 no. 6 doi:10.1128/microbiolspec.MDNA3-0038-2014
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FIGURE 3

Arrangement of and the silent cassettes in B31, Far04, and JD1. Cassette region sequences are shown in green, whereas flanking 5′ and 3′ sequences and homologous 5′ sequences at the beginning of the silent cassette arrays are shown in red. Arrows indicate the locations of inverted repeats. Arrowheads correspond with frameshifts, with the blue arrowheads indicating frameshifts between silent cassettes and red arrowheads showing those located within silent cassettes (as also indicated by the and designations of the ORFs before and after the frameshift). The B31 silent cassette 11 contains a stop codon (red asterisk). doi:10.1128/microbiolspec.MDNA3-0038-2014.f3

Source: microbiolspec December 2014 vol. 2 no. 6 doi:10.1128/microbiolspec.MDNA3-0038-2014
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FIGURE 4

Localization of the VRs in the three-dimensional structure of the B31 allele VlsE1. (A) Ribbon diagram showing the abundance of alpha helices and the location of the cassette VR (yellow) and IRs (blue). Amino acids encoded by the direct repeats at either end of the cassette region are shown in red. The protein is anchored to the outer membrane by lipid moieties associated with the N-terminal cysteine. A schematic of the cassette region and flanking sequences is shown below the 3D structure. (B) Space-filling models indicating the locations of VRs 1 through 6. The VRs cover most of the membrane distal surface of the protein. The bottom panel shows the locations of variable amino acid residues in yellow. Modified from Eicken et al. ( 46 ) with permission. doi:10.1128/microbiolspec.MDNA3-0038-2014.f4

Source: microbiolspec December 2014 vol. 2 no. 6 doi:10.1128/microbiolspec.MDNA3-0038-2014
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FIGURE 5

Properties of the locus potentially involved in recombination and regulation of transcription. (A) Inverted repeat between and the silent cassettes of B31 (48; Norris SJ, Howell JK, unpublished data). The predicted stem–loop structure includes the –35 region of the promoter. (B) G+C content and GC skew of and the silent cassettes in B31. (C) Lack of conservation of the direct repeat sequences in Lyme disease suggests a limited role of these regions in recombination ( 38 ). Representative sequences are shown. doi:10.1128/microbiolspec.MDNA3-0038-2014.f5

Source: microbiolspec December 2014 vol. 2 no. 6 doi:10.1128/microbiolspec.MDNA3-0038-2014
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FIGURE 6

Model for the evolution of and related genes in . It is hypothesized that a common ancestor of LB and RF organisms contained single copies of primordial and homologs. Following the divergence of LB and RF groups, these precursor genes duplicated and developed into the system and in a primordial LB organism, and into the VMP system and in a primordial RF ancestor. Each of these antigenic variation systems and related surface proteins continued to evolve and diverge under the pressure of immune selection. doi:10.1128/microbiolspec.MDNA3-0038-2014.f6

Source: microbiolspec December 2014 vol. 2 no. 6 doi:10.1128/microbiolspec.MDNA3-0038-2014
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Tables

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TABLE 1

Stages of Lyme borreliosis.

Source: microbiolspec December 2014 vol. 2 no. 6 doi:10.1128/microbiolspec.MDNA3-0038-2014

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