Maintenance of Antibody to Pathogen Epitopes Generated by Segmental Gene Conversion Is Highly Dynamic during Long-Term Persistent Infection

Zhuang, Yan; Futse, James E.; Brown, Wendy C.; Brayton, Kelly A.; Palmer, Guy H.

doi:10.1128/iai.00913-07

Cited by 25 publications

(32 citation statements)

References 35 publications

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“…The continuous generation of high numbers of low-affinity antibodies, due to the flexible tertiary structure of the microdomains, may preclude B-lymphocyte receptor affinity maturation and the generation of plasma cells producing high-affinity antibodies and high-affinity memory. This is consistent with two observations: (i) HVR microdomainspecific antibodies are short-lived (36), and (ii) individual Msp2 variants can be expressed more than once in persistent infection following the decline of specific antibody (30). Thus, the random coil structure of the Msp2 HVR may expand the potential variant repertoire both by allowing mosaic formation and by allowing reexpression of the same variant due to low-affinity binding.…”

Section: Discussionsupporting

confidence: 77%

“…This is consistent with the role of disordered protein regions in eukaryotic cell signaling, where they have been shown to mediate highly specific but low-affinity interactions (33,35). This has clear relevance for the development of antibodies to Msp2 variant microdomains, which are present at high titers but transient (30,36). The continuous generation of high numbers of low-affinity antibodies, due to the flexible tertiary structure of the microdomains, may preclude B-lymphocyte receptor affinity maturation and the generation of plasma cells producing high-affinity antibodies and high-affinity memory.…”

Section: Discussionsupporting

confidence: 61%

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Structural Basis for Recombinatorial Permissiveness in the Generation of Anaplasma marginale Msp2 Antigenic Variants

Graça

Silva

Kostyukova³

et al. 2016

Infect Immun

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Sequential expression of outer membrane protein antigenic variants is an evolutionarily convergent mechanism used by bacterial pathogens to escape host immune clearance and establish persistent infection. Variants must be sufficiently structurally distinct to escape existing immune effectors yet retain the core structural elements required for localization and function within the outer membrane. We examined this balance using Anaplasma marginale, which generates antigenic variants in the outer membrane protein Msp2 using gene conversion. The overwhelming majority of Msp2 variants expressed during long-term persistent infection are mosaics, derived by recombination of oligonucleotide segments from multiple alleles to form unique hypervariable regions (HVR). As a result, the mosaics are not under long-term selective pressure to encode a functional protein; consequently, we hypothesized that the Msp2 HVR is structurally permissive for mosaic expression. Using an integrated approach of predictive modeling with determination of the native Msp2 protein structure and function, we demonstrate that structured elements, most notably, ␤-sheets, are significantly concentrated in the highly conserved N-and C-terminal domains. In contrast, the HVR is overwhelmingly a random coil, with the structured ␣-helices and ␤-sheets being confined to the genomically defined structural tethers that separate the antigenically variable microdomains. This structure is supported by the surface exposure of the HVR microdomains and the slow diffusion-type porin function in native Msp2. Importantly, the predominance of the random coil provides plasticity for the formation of functional HVR mosaics and realization of the full potential of segmental gene conversion to dramatically expand the variant repertoire. Highly antigenically variable microbes use a diversity of mechanisms to generate molecules that allow escape from host immune effectors and result in long-term persistence. Bacterial pathogens across multiple genera, including Anaplasma, Borrelia, Neisseria, and Treponema, generate outer membrane protein variants by gene conversion, resulting in novel expressed surface antigens (1-3). The potential repertoire of antigenic variants is determined by the number of donor alleles in the pathogen genome combined with the occurrence of segmental recombinatorial events that can generate unique expression site mosaics (1-3). Notably, segmental gene conversion results in expressed variants not represented by any one allele but generated in situ by recombination of donated oligonucleotides derived from different alleles. This generation of unique mosaics can tremendously expand the potential antigenic repertoire. The number of alleles encoding unique Msp2 variants in Anaplasma marginale is Ͻ10, and segmental recombination using oligonucleotide segments derived from these alleles allows the generation of Ͼ1,000 potential variants (4-6). Similarly, segmental gene conversion in Treponema pallidum exponentially increases the potential number of TpK varia...

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Section: Discussionsupporting

confidence: 77%

Section: Discussionsupporting

confidence: 61%

Structural Basis for Recombinatorial Permissiveness in the Generation of Anaplasma marginale Msp2 Antigenic Variants

Graça

Silva

Kostyukova³

et al. 2016

Infect Immun

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“…The N-and C-terminal regions, which form ␤ barrels, are highly conserved among all variants, and the encoding 5= and 3= domains provide the "anchor" points for gene conversion (8,17). Although conserved, these N-and C-terminal regions are poorly immunogenic and only very weakly bound by antibody from either natural infection or in immunized and protected animals (1,3,43). In contrast, the hydrophilic central region is surface exposed and highly immunogenic but also highly variable among donor alleles within a strain and alleles across strains (1, 3, 16, 34, 43).…”

Section: Discussionmentioning

confidence: 99%

Expansion of Variant Diversity Associated with a High Prevalence of Pathogen Strain Superinfection under Conditions of Natural Transmission

Ueti¹,

Tan

Broschat

et al. 2012

Infect Immun

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ABSTRACTSuperinfection occurs when a second, genetically distinct pathogen strain infects a host that has already mounted an immune response to a primary strain. For antigenically variant pathogens, the primary strain itself expresses a broad diversity of variants over time. Thus, successful superinfection would require that the secondary strain express a unique set of variants. We tested this hypothesis under conditions of natural transmission in both temperate and tropical regions where, respectively, single-strain infections and strain superinfections of the tick-borne pathogenAnaplasma marginalepredominate. Our conclusion that strain superinfection is associated with a significant increase in variant diversity is supported by progressive analysis of variant composition: (i) animals with naturally acquired superinfection had a statistically significantly greater number of unique variant sequences than animals either experimentally infected with single strains or infected with a single strain naturally, (ii) the greater number of unique sequences reflected a statistically significant increase in primary structural diversity in the superinfected animals, and (iii) the increase in primary structural diversity reflected increased combinations of the newly identified hypervariable microdomains. The role of population immunity in establishing temporal and spatial patterns of infection and disease has been well established. The results of the present study, which examined strain structure under conditions of natural transmission and population immunity, support that high levels of endemicity also drive pathogen divergence toward greater strain diversity.

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“…JQ933614 to JQ933796) (5,12). Msp2 HVR microdomains 1 and 2 encompass the immunodominant B cell epitopes in the HVRs encoded by the allelic repertoire in the St. Maries strain (13,14) and are defined by flanking conserved amino acids, previously designated "structural tethers" (Fig. 2).…”

Section: Methodsmentioning

confidence: 99%

Primary Structural Variation in Anaplasma marginale Msp2 Efficiently Generates Immune Escape Variants

et al. 2015

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Antigenic variation allows microbial pathogens to evade immune clearance and establish persistent infection. Anaplasma marginale utilizes gene conversion of a repertoire of silent msp2 alleles into a single active expression site to encode unique Msp2 variants. As the genomic complement of msp2 alleles alone is insufficient to generate the number of variants required for persistence, A. marginale uses segmental gene conversion, in which oligonucleotide segments from multiple alleles are recombined into the expression site to generate a novel msp2 mosaic not represented elsewhere in the genome. Whether these segmental changes are sufficient to evade a broad antibody response is unknown. We addressed this question by identifying Msp2 variants that differed in primary structure within the immunogenic hypervariable region microdomains and tested whether they represented true antigenic variants. The minimal primary structural difference between variants was a single amino acid resulting from a codon insertion, and overall, the amino acid identity among paired microdomains ranged from 18 to 92%. Collectively, 89% of the expressed structural variants were also antigenic variants across all biological replicates, independent of a specific host major histocompatibility complex haplotype. Biological relevance is supported by the following: (i) all structural variants were expressed during infection of a natural host, (ii) the structural variation observed in the microdomains corresponded to the mean length of variants generated by segmental gene conversion, and (iii) antigenic variants were identified using a broad antibody response that developed during infection of a natural host. The findings demonstrate that segmental gene conversion efficiently generates Msp2 antigenic variants.

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Maintenance of Antibody to Pathogen Epitopes Generated by Segmental Gene Conversion Is Highly Dynamic during Long-Term Persistent Infection

Cited by 25 publications

References 35 publications

Structural Basis for Recombinatorial Permissiveness in the Generation of Anaplasma marginale Msp2 Antigenic Variants

Structural Basis for Recombinatorial Permissiveness in the Generation of Anaplasma marginale Msp2 Antigenic Variants

Expansion of Variant Diversity Associated with a High Prevalence of Pathogen Strain Superinfection under Conditions of Natural Transmission

Primary Structural Variation in Anaplasma marginale Msp2 Efficiently Generates Immune Escape Variants

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