User:Marvin O'Neal/VlsE
From Proteopedia
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| - | <scene name='Studio:G5SecL01/Main_image_vlse/1'>VlsE</scene> is a surface lipoprotein of Borrelia burgdorferi, the causative agent of [http://en.wikipedia.org/wiki/Lyme_disease Lyme Disease]. It undergoes [http://en.wikipedia.org/wiki/Antigenic_variation antigenic variation] ostensibly important in evasion of the host’s immune system. In addition, the protein is used for Lyme disease diagnosis. It is composed of four similar subunits each possessing two invariable domains and one variable domain <ref name="A">PMID:10569796</ref> . The variable domain contains six variable regions (VR<sub>1</sub>-VR<sub>6</sub>), and six invariable regions (IR<sub>1</sub>-IR<sub>6</sub>). Research suggests that the protein may exist as a dimer where the C & N monomeric termini neighbor each other forming the membrane proximal portion of the protein, and the variable regions form the membrane distal portion <ref>PMID:11923306</ref> <ref>PMID: 11716485</ref>. The invariable regions are largely embedded in the protein and remain relatively unchanged within the host and across strains. The variable regions encompass 37% of the VlsE’s exposed surface area despite comprising only 25% of the protein <ref name="A" /> <ref | + | <scene name='Studio:G5SecL01/Main_image_vlse/1'>VlsE</scene> is a surface lipoprotein of Borrelia burgdorferi, the causative agent of [http://en.wikipedia.org/wiki/Lyme_disease Lyme Disease]. It undergoes [http://en.wikipedia.org/wiki/Antigenic_variation antigenic variation] ostensibly important in evasion of the host’s immune system. In addition, the protein is used for Lyme disease diagnosis. It is composed of four similar subunits each possessing two invariable domains and one variable domain <ref name="A">PMID:10569796</ref>. The variable domain contains six variable regions (VR<sub>1</sub>-VR<sub>6</sub>), and six invariable regions (IR<sub>1</sub>-IR<sub>6</sub>). Research suggests that the protein may exist as a dimer where the C & N monomeric termini neighbor each other forming the membrane proximal portion of the protein, and the variable regions form the membrane distal portion <ref name="B">PMID:11923306</ref> <ref name="C">PMID:11716485</ref>. The invariable regions are largely embedded in the protein and remain relatively unchanged within the host and across strains. The variable regions encompass 37% of the VlsE’s exposed surface area despite comprising only 25% of the protein <ref name="A" /> <ref name="B" />. However, 50% of the VR surface area is exposed while IR<sub>6</sub>, the immunodominant portion, exposes just 13.7% of its surface area. This leaves only <scene name='Studio:G5SecL01/Ir_6_4_residues/1'>four amino residues</scene> of the antigenic IR<sub>6</sub> unprotected; lysine-276, glutamine-279, lysine-291, and lysine-294. Thus, it is almost entirely embedded in the protein and <scene name='Studio:G5SecL01/Ir6_embedded/1'>sheilded by the variable regions </scene> <ref name="B" />. <br> |
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| - | The variable regions undergo a recombination event stimulated by the host’s cytokines and absence of those cytokines results in a decreased bacterial burden <ref>PMID:11544329</ref>. This leads to variation with an estimated 10<sup>30</sup> possible combinations, far exceeding the number of antibodies found in the human immune system. While the VR does exhibit antigenicity, this recombination makes it unlikely that enough of a single VR variation will be present in large enough supply to lead to an immunodominant variable region <ref>PMID:10553085</ref>. IR<sub>6</sub>, however, exhibits immunodominance while IR<sub>1</sub>-IR<sub>5</sub> are primarily nonantigenic in humans. Thus, shielding of the immunodominant IR<sub>6</sub> by VR regions not subject to antibody response allows for IR<sub>6</sub> to elicit an immune response while remaining inaccessible to antibody binding. Research suggests that the 26 amino residues of <scene name='Studio:G5SecL01/Ir6_with_epitope/1'>IR6</scene> may function as a single epitope with a central alpha helical core <ref | + | The variable regions undergo a recombination event stimulated by the host’s cytokines and absence of those cytokines results in a decreased bacterial burden <ref name="D">PMID:11544329</ref>. This leads to variation with an estimated 10<sup>30</sup> possible combinations, far exceeding the number of antibodies found in the human immune system. While the VR does exhibit antigenicity, this recombination makes it unlikely that enough of a single VR variation will be present in large enough supply to lead to an immunodominant variable region <ref name="E">PMID:10553085</ref>. IR<sub>6</sub>, however, exhibits immunodominance while IR<sub>1</sub>-IR<sub>5</sub> are primarily nonantigenic in humans. Thus, shielding of the immunodominant IR<sub>6</sub> by VR regions not subject to antibody response allows for IR<sub>6</sub> to elicit an immune response while remaining inaccessible to antibody binding. Research suggests that the 26 amino residues of <scene name='Studio:G5SecL01/Ir6_with_epitope/1'>IR6</scene> may function as a single epitope with a central alpha helical core <ref name="B" /> <ref name="D" /> <ref name="F">PMID:10722641</ref>. |
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| - | VlsE is essential to the persistence and virulence of Lyme disease and is upregulated under humoral immune pressure <ref>PMID:17714442</ref> <ref>PMID:15385475</ref>. While the exact mechanism for immune evasion remains unknown several theories have been put forth. One popular theory is that VlsE masks other surface antigens by coating the surface of the bacteria, thereby sterically blocking the antigens from antibody binding. This is similar to other pathogens with variable regions, such as the [http://en.wikipedia.org/wiki/Trypanosoma_brucei protozoa] responsible for African sleeping sickness and also the [http://en.wikipedia.org/wiki/Neisseria_gonorrhoeae bacterium] that causes gonorrhea. However, recent studies have cast doubt on this theory. An alternate theory provides that VlsE directly stimulates B cell antibody production independent of T-cells. The robust response elicited is thought to override antibody production against other antigens <ref | + | VlsE is essential to the persistence and virulence of Lyme disease and is upregulated under humoral immune pressure <ref name="G">PMID:17714442</ref> <ref name="H">PMID:15385475</ref>. While the exact mechanism for immune evasion remains unknown several theories have been put forth. One popular theory is that VlsE masks other surface antigens by coating the surface of the bacteria, thereby sterically blocking the antigens from antibody binding. This is similar to other pathogens with variable regions, such as the [http://en.wikipedia.org/wiki/Trypanosoma_brucei protozoa] responsible for African sleeping sickness and also the [http://en.wikipedia.org/wiki/Neisseria_gonorrhoeae bacterium] that causes gonorrhea. However, recent studies have cast doubt on this theory. An alternate theory provides that VlsE directly stimulates B cell antibody production independent of T-cells. The robust response elicited is thought to override antibody production against other antigens <ref name="G" />. |
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| - | Throughout the course of the disease IR<sub>6</sub> produces a strong antibody response that can be identified from early to late phases, and which lasts for months to years following treatment. Applications in diagnostic testing have been identified as a result of this strong immune response and IR<sub>6</sub>’s relative invariability across strains <ref>PMID:10565920</ref> <ref | + | Throughout the course of the disease IR<sub>6</sub> produces a strong antibody response that can be identified from early to late phases, and which lasts for months to years following treatment. Applications in diagnostic testing have been identified as a result of this strong immune response and IR<sub>6</sub>’s relative invariability across strains <ref name="I">PMID:10565920</ref> <ref name="F" />. A C<sub>6</sub> ELISA test has been developed which uses a 26-mer synthetic peptide with the IR<sub>6</sub> sequence. Results show 99% specificity and 100% precision with high sensitivity. In fact, OspA vaccination does not influence C6 specificity; therefore, C<sub>6</sub> ELISA tests are valuable diagnostic tools <ref name="I" />. The [http://www.cdc.gov/lyme/healthcare/clinician_twotier.html CDC] currently recommends a two-step test incorporating first a polyvalent, whole-cell sonicate (WCS) immunofluorescent assay. If results are positive, this is followed by IgG and IgM WCS Western blots to eliminate false positives <ref name="J">PMID:21865190</ref>. Therefore, this one-step ELISA test presents an accurate and economical alternative to the current two-step model <ref name="I" />. <br> |
Revision as of 01:37, 30 April 2012
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Contents |
Structural Overview
is a surface lipoprotein of Borrelia burgdorferi, the causative agent of Lyme Disease. It undergoes antigenic variation ostensibly important in evasion of the host’s immune system. In addition, the protein is used for Lyme disease diagnosis. It is composed of four similar subunits each possessing two invariable domains and one variable domain [1]. The variable domain contains six variable regions (VR1-VR6), and six invariable regions (IR1-IR6). Research suggests that the protein may exist as a dimer where the C & N monomeric termini neighbor each other forming the membrane proximal portion of the protein, and the variable regions form the membrane distal portion [2] [3]. The invariable regions are largely embedded in the protein and remain relatively unchanged within the host and across strains. The variable regions encompass 37% of the VlsE’s exposed surface area despite comprising only 25% of the protein [1] [2]. However, 50% of the VR surface area is exposed while IR6, the immunodominant portion, exposes just 13.7% of its surface area. This leaves only of the antigenic IR6 unprotected; lysine-276, glutamine-279, lysine-291, and lysine-294. Thus, it is almost entirely embedded in the protein and [2].
Antigenicity
The variable regions undergo a recombination event stimulated by the host’s cytokines and absence of those cytokines results in a decreased bacterial burden [4]. This leads to variation with an estimated 1030 possible combinations, far exceeding the number of antibodies found in the human immune system. While the VR does exhibit antigenicity, this recombination makes it unlikely that enough of a single VR variation will be present in large enough supply to lead to an immunodominant variable region [5]. IR6, however, exhibits immunodominance while IR1-IR5 are primarily nonantigenic in humans. Thus, shielding of the immunodominant IR6 by VR regions not subject to antibody response allows for IR6 to elicit an immune response while remaining inaccessible to antibody binding. Research suggests that the 26 amino residues of may function as a single epitope with a central alpha helical core [2] [4] [6].
Function in Immune System Evasion
VlsE is essential to the persistence and virulence of Lyme disease and is upregulated under humoral immune pressure [7] [8]. While the exact mechanism for immune evasion remains unknown several theories have been put forth. One popular theory is that VlsE masks other surface antigens by coating the surface of the bacteria, thereby sterically blocking the antigens from antibody binding. This is similar to other pathogens with variable regions, such as the protozoa responsible for African sleeping sickness and also the bacterium that causes gonorrhea. However, recent studies have cast doubt on this theory. An alternate theory provides that VlsE directly stimulates B cell antibody production independent of T-cells. The robust response elicited is thought to override antibody production against other antigens [7].
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C6 Diagnostic Testing
Throughout the course of the disease IR6 produces a strong antibody response that can be identified from early to late phases, and which lasts for months to years following treatment. Applications in diagnostic testing have been identified as a result of this strong immune response and IR6’s relative invariability across strains [9] [6]. A C6 ELISA test has been developed which uses a 26-mer synthetic peptide with the IR6 sequence. Results show 99% specificity and 100% precision with high sensitivity. In fact, OspA vaccination does not influence C6 specificity; therefore, C6 ELISA tests are valuable diagnostic tools [9]. The CDC currently recommends a two-step test incorporating first a polyvalent, whole-cell sonicate (WCS) immunofluorescent assay. If results are positive, this is followed by IgG and IgM WCS Western blots to eliminate false positives [10]. Therefore, this one-step ELISA test presents an accurate and economical alternative to the current two-step model [9].
Additional Links
Lyme Disease Microbiology
CDC Lyme Disease Page
Lyme Disease
Ecology, Epidemiology, and Prevention of Lyme Disease- CDC
Antigenic Variation
References
- ↑ 1.0 1.1 Liang FT, Philipp MT. Analysis of antibody response to invariable regions of VlsE, the variable surface antigen of Borrelia burgdorferi. Infect Immun. 1999 Dec;67(12):6702-6. PMID:10569796
- ↑ 2.0 2.1 2.2 2.3 Eicken C, Sharma V, Klabunde T, Lawrenz MB, Hardham JM, Norris SJ, Sacchettini JC. Crystal structure of Lyme disease variable surface antigen VlsE of Borrelia burgdorferi. J Biol Chem. 2002 Jun 14;277(24):21691-6. Epub 2002 Mar 28. PMID:11923306 doi:10.1074/jbc.M201547200
- ↑ Jones K, Guidry J, Wittung-Stafshede P. Characterization of surface antigen from Lyme disease spirochete Borrelia burgdorferi. Biochem Biophys Res Commun. 2001 Nov 30;289(2):389-94. PMID:11716485 doi:10.1006/bbrc.2001.5983
- ↑ 4.0 4.1 Anguita J, Thomas V, Samanta S, Persinski R, Hernanz C, Barthold SW, Fikrig E. Borrelia burgdorferi-induced inflammation facilitates spirochete adaptation and variable major protein-like sequence locus recombination. J Immunol. 2001 Sep 15;167(6):3383-90. PMID:11544329
- ↑ Liang FT, Alvarez AL, Gu Y, Nowling JM, Ramamoorthy R, Philipp MT. An immunodominant conserved region within the variable domain of VlsE, the variable surface antigen of Borrelia burgdorferi. J Immunol. 1999 Nov 15;163(10):5566-73. PMID:10553085
- ↑ 6.0 6.1 Liang FT, Philipp MT. Epitope mapping of the immunodominant invariable region of Borrelia burgdorferi VlsE in three host species. Infect Immun. 2000 Apr;68(4):2349-52. PMID:10722641
- ↑ 7.0 7.1 Bankhead T, Chaconas G. The role of VlsE antigenic variation in the Lyme disease spirochete: persistence through a mechanism that differs from other pathogens. Mol Microbiol. 2007 Sep;65(6):1547-58. Epub 2007 Aug 21. PMID:17714442 doi:10.1111/j.1365-2958.2007.05895.x
- ↑ Liang FT, Yan J, Mbow ML, Sviat SL, Gilmore RD, Mamula M, Fikrig E. Borrelia burgdorferi changes its surface antigenic expression in response to host immune responses. Infect Immun. 2004 Oct;72(10):5759-67. PMID:15385475 doi:10.1128/IAI.72.10.5759-5767.2004
- ↑ 9.0 9.1 9.2 Liang FT, Steere AC, Marques AR, Johnson BJ, Miller JN, Philipp MT. Sensitive and specific serodiagnosis of Lyme disease by enzyme-linked immunosorbent assay with a peptide based on an immunodominant conserved region of Borrelia burgdorferi vlsE. J Clin Microbiol. 1999 Dec;37(12):3990-6. PMID:10565920
- ↑ Branda JA, Linskey K, Kim YA, Steere AC, Ferraro MJ. Two-tiered antibody testing for Lyme disease with use of 2 enzyme immunoassays, a whole-cell sonicate enzyme immunoassay followed by a VlsE C6 peptide enzyme immunoassay. Clin Infect Dis. 2011 Sep;53(6):541-7. PMID:21865190 doi:10.1093/cid/cir464
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