Antigenic Variation in Bacterial Pathogens

Palmer, Guy H.; Bankhead, Troy; Seifert, H. Steven

doi:10.1128/microbiolspec.vmbf-0005-2015

Cited by 53 publications

(40 citation statements)

References 191 publications

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“…Two potential, not mutually exclusive, mechanisms of vls-mediated avoidance have been proposed (13,17,(19)(20)(21). The first is vls-mediated masking whereby VlsE may physically shield B. burgdorferi surface antigens from antibody.…”

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confidence: 99%

Antibody Response to Lyme Disease Spirochetes in the Context of VlsE-Mediated Immune Evasion

et al. 2017

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Lyme disease (LD), the most prevalent tick-borne illness in North America, is caused by Borrelia burgdorferi. The long-term survival of B. burgdorferi spirochetes in the mammalian host is achieved though VlsE-mediated antigenic variation. It is mathematically predicted that a highly variable surface antigen prolongs bacterial infection sufficiently to exhaust the immune response directed toward invariant surface antigens. If the prediction is correct, it is expected that the antibody response to B. burgdorferi invariant antigens will become nonprotective as B. burgdorferi infection progresses. To test this assumption, changes in the protective efficacy of the immune response to B. burgdorferi surface antigens were monitored via a superinfection model over the course of 70 days. B. burgdorferi-infected mice were subjected to secondary challenge by heterologous B. burgdorferi at different time points postinfection (p.i.). When the infected mice were superinfected with a VlsEdeficient clone (ΔVlsE) at day 28 p.i., the active anti-B. burgdorferi immune response did not prevent ΔVlsE-induced spirochetemia. In contrast, most mice blocked culture-detectable spirochetemia induced by wild-type B. burgdorferi (WT), indicating that VlsE was likely the primary target of the antibody response. As the B. burgdorferi infection further progressed, however, reversed outcomes were observed. At day 70 p.i. the host immune response to non-VlsE antigens became sufficiently potent to clear spirochetemia induced by ΔVlsE and yet failed to prevent WT-induced spirochetemia. To test if any significant changes in the anti-B. burgdorferi antibody repertoire accounted for the observed outcomes, global profiles of antibody specificities were determined. However, comparison of mimotopes revealed no major difference between day 28 and day 70 antibody repertoires.

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confidence: 99%

Antibody Response to Lyme Disease Spirochetes in the Context of VlsE-Mediated Immune Evasion

et al. 2017

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“…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)(2)(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)(2)(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.…”

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confidence: 99%

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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“…This is as a result of replication slipping or slippage errors and repairs of simple tandem nucleotide repeats involving either the di-, or tri-or tetra-nucleotides. 86 • Neisseria is able to take up and incorporate environmental DNA into its genomes. 83 These are why an effective vaccine against Neisseria infections is not yet developed.…”

Section: Neisseriamentioning

confidence: 99%

<p>Immunoinformatics and Vaccine Development: An Overview</p>

Oli

Obialor

Ifeanyichukwu

et al. 2020

ITT

158

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The use of vaccines have resulted in a remarkable improvement in global health. It has saved several lives, reduced treatment costs and raised the quality of animal and human lives. Current traditional vaccines came empirically with either vague or completely no knowledge of how they modulate our immune system. Even at the face of potential vaccine design advance, immune-related concerns (as seen with specific vulnerable populations, cases of emerging/reemerging infectious disease, pathogens with complex lifecycle and antigenic variability, need for personalized vaccinations, and concerns for vaccines' immunological safety -specifically vaccine likelihood to trigger non-antigen-specific responses that may cause autoimmunity and vaccine allergy) are being raised. And these concerns have driven immunologists toward research for a better approach to vaccine design that will consider these challenges. Currently, immunoinformatics has paved the way for a better understanding of some infectious disease pathogenesis, diagnosis, immune system response and computational vaccinology. The importance of this immunoinformatics in the study of infectious diseases is diverse in terms of computational approaches used, but is united by common qualities related to host-pathogen relationship. Bioinformatics methods are also used to assign functions to uncharacterized genes which can be targeted as a candidate in vaccine design and can be a better approach toward the inclusion of women that are pregnant into vaccine trials and programs. The essence of this review is to give insight into the need to focus on novel computational, experimental and computation-driven experimental approaches for studying of host-pathogen interactions and thus making a case for its use in vaccine development.

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Antigenic Variation in Bacterial Pathogens

Cited by 53 publications

References 191 publications

Antibody Response to Lyme Disease Spirochetes in the Context of VlsE-Mediated Immune Evasion

Antibody Response to Lyme Disease Spirochetes in the Context of VlsE-Mediated Immune Evasion

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

<p>Immunoinformatics and Vaccine Development: An Overview</p>

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