SB2013 L04gr5: Difference between revisions
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Figure 2 shows the possible dimerization of VlsE. | Figure 2 shows the possible dimerization of VlsE. | ||
=Antigenic Variation= | =Antigenic Variation= | ||
Antigenic variation is the process by which an organism is able to evade its host’s immune system. The antigenic variation that occurs in VlsE uses a complex genetic conversion mechanism that is seen to be concentrated in the VRs. The complex genetic system for VlsE is located near the right telomere on a 28-kb linear plasmid (lp28-1) in strains of ''B. burgdorferi''. This [http://en.wikipedia.org/wiki/Locus_%28genetics%29 locus] has been shown to be a crucial element for the persistence and virulence of Lyme disease (Bankhead and Chaconas 2007). The vls antigenic variation locus consists of a vls expression site (vlsE) and 15 silent vls cassettes that reside just upstream of the site. The vlsE cassette region, which is the variable domain and does not include the invariable amino or carboxyl termini, has approximately 92% DNA sequence identity with the silent vls cassettes. However, the silent vls cassettes lack promoter sequences and are therefore not expressed. Throughout the course of infection, the sequences for the flanking termini and the silent vls cassettes are conserved while the vlsE sequence is recombined. This suggests that the genetic variation mechanism occurs by copying segments of the 15 silent vls cassettes and completely replacing corresponding segments of vlsE sequences. The resulting differences are centralized in the highly variable regions of the vls cassettes. This allows for the constant evolution of the VR structures and evades the antibodies of the host immune system | Antigenic variation is the process by which an organism is able to evade its host’s immune system. The antigenic variation that occurs in VlsE uses a complex genetic conversion mechanism that is seen to be concentrated in the VRs. The complex genetic system for VlsE is located near the right telomere on a 28-kb linear plasmid (lp28-1) in strains of ''B. burgdorferi''. This [http://en.wikipedia.org/wiki/Locus_%28genetics%29 locus] has been shown to be a crucial element for the persistence and virulence of Lyme disease (Bankhead and Chaconas 2007). The ''vls'' antigenic variation locus consists of a ''vls'' expression site (''vlsE'') and 15 silent vls cassettes that reside just upstream of the site. The ''vlsE'' cassette region, which is the variable domain and does not include the invariable amino or carboxyl termini, has approximately 92% DNA sequence identity with the silent vls cassettes. However, the silent ''vls'' cassettes lack promoter sequences and are therefore not expressed. Throughout the course of infection, the sequences for the flanking termini and the silent ''vls'' cassettes are conserved while the vlsE sequence is recombined. This suggests that the genetic variation mechanism occurs by copying segments of the 15 silent vls cassettes and completely replacing corresponding segments of ''vlsE'' sequences. The resulting differences are centralized in the highly variable regions of the ''vls'' cassettes. This allows for the constant evolution of the VR structures and evades the antibodies of the host immune system <ref name="Zhang and Norris">. | ||
==''Variable Regions''== | ==''Variable Regions''== | ||
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Interspersed in the variable regions of the variable domain are six invariable regions (IR1-IR6). Although located on the membrane distal region of the protein, the IRs are buried within the protein and have little exposure to the surface. The IRs might be further hidden from surface exposure due to the possible dimerization of VlsE, forming a shield at the monomer-monomer interface (Eicken et al 2002). These six IRs do not undergo changes during antigenic variation and are present in many strains and genospecies of ''B. burgdorferi''. | Interspersed in the variable regions of the variable domain are six invariable regions (IR1-IR6). Although located on the membrane distal region of the protein, the IRs are buried within the protein and have little exposure to the surface. The IRs might be further hidden from surface exposure due to the possible dimerization of VlsE, forming a shield at the monomer-monomer interface (Eicken et al 2002). These six IRs do not undergo changes during antigenic variation and are present in many strains and genospecies of ''B. burgdorferi''. | ||
<scene name='SB2013_L04gr5/Ir6/1'>IR6</scene>, the second least exposed region composed of 26 amino acids, has been found to be the most conserved IR and the most immunogenic as observed in studies involving monkeys and humans. In a study conducted by Liang et al., serum samples from monkeys were infected by the bite of ''Ixodes scapularis'' nymphal ticks. The results showed a robust response to IR6 and little to no response to the remaining IRs. Similarly, only IR6 elicited a strong immune response in infected humans. Clearly, due to its highly conserved structure and immunodominance, IR6 is important to the functionality of ''B. | <scene name='SB2013_L04gr5/Ir6/1'>IR6</scene>, the second least exposed region composed of 26 amino acids, has been found to be the most conserved IR and the most immunogenic as observed in studies involving monkeys and humans. In a study conducted by Liang et al., serum samples from monkeys were infected by the bite of ''Ixodes scapularis'' nymphal ticks. The results showed a robust response to IR6 and little to no response to the remaining IRs. Similarly, only IR6 elicited a strong immune response in infected humans. Clearly, due to its highly conserved structure and immunodominance, IR6 is important to the functionality of ''B. burgdorferi'' and therefore requires its strategic placement indicated in the crystallized structure (Eicken et al 2002). In mice, however, a strong response was detected across IRs 6, 2, and 4, but not in IRs 1, 3, and 5. (Liang et al 1999 A), thus demonstrating the importance of IR6 across many species and indicating that further research into the fuctions of IRs 2 and 4 is needed. | ||
The high immunogenicity effect of IR6 is thought to only occur in dead bacteria due to its low maximal theoretical surface exposure in living ''B. borgderfuri'' (13.7%). Interaction with anti-IR6 antibodies would be limited to the exposed <scene name='SB2013_L04gr5/Ir6_residues/1'>amino acid residues</scene>, Lys-274, Gln-279, Lys-291,Lys-294 (Eicken). These amino acids would be the likely targets of the host immune response. The immunodominant nature of VlsE, especially in IR6, makes it a viable diagnostic tool.<ref name="Marangoni" /> | The high immunogenicity effect of IR6 is thought to only occur in dead bacteria due to its low maximal theoretical surface exposure in living ''B. borgderfuri'' (13.7%). Interaction with anti-IR6 antibodies would be limited to the exposed <scene name='SB2013_L04gr5/Ir6_residues/1'>amino acid residues</scene>, Lys-274, Gln-279, Lys-291,Lys-294 (Eicken). These amino acids would be the likely targets of the host immune response. The immunodominant nature of VlsE, especially in IR6, makes it a viable diagnostic tool.<ref name="Marangoni" /> | ||
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9.<ref name="Liang B">Liang F, Steere A, Marques A, Johnson B, Miller J, Philipp M. 1999. 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. Journal of Clinical Microbiology.37(12): 3990-3996. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/10565920 10565920]</ref> | 9.<ref name="Liang B">Liang F, Steere A, Marques A, Johnson B, Miller J, Philipp M. 1999. 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. Journal of Clinical Microbiology.37(12): 3990-3996. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/10565920 10565920]</ref> | ||
10.<ref name="Chandra">Chandra A, Latov N, Wormser G, Marques A, Alaedini A. 2011. Epitope mapping of antibodies to VlsE protein of ''Borrelia burgdorferi'' in post-Lyme disease syndrome. Clinical Immunology. 141(1): 103-110. PMID[http://www.ncbi.nlm.nih.gov/pubmed/21778118 21778118]</ref> | 10.<ref name="Chandra">Chandra A, Latov N, Wormser G, Marques A, Alaedini A. 2011. Epitope mapping of antibodies to VlsE protein of ''Borrelia burgdorferi'' in post-Lyme disease syndrome. Clinical Immunology. 141(1): 103-110. PMID[http://www.ncbi.nlm.nih.gov/pubmed/21778118 21778118]</ref> | ||
11.<ref name="Marangoni">Marangoni A, Sambri V, Accardo S, Cavrini F, Mondardini V, Moroni A, Storni E, Cevenini R. 2006. A Decrease in the Immunoglobulin G Antibody Response Against against the VlsE Protein of Borrelia burgdorferi Sensu Lato Correlates with the Resolution of Clinical Signs in Antibiotic-Treated Patients with Early Lyme Disease. Clinical and Vaccine Immunology. 13(4): 525-529. PMID[http://www.ncbi.nlm.nih.gov/pubmed/16603623 16603623]</ref> | 11.<ref name="Marangoni">Marangoni A, Sambri V, Accardo S, Cavrini F, Mondardini V, Moroni A, Storni E, Cevenini R. 2006. A Decrease in the Immunoglobulin G Antibody Response Against against the VlsE Protein of ''Borrelia burgdorferi'' Sensu Lato Correlates with the Resolution of Clinical Signs in Antibiotic-Treated Patients with Early Lyme Disease. Clinical and Vaccine Immunology. 13(4): 525-529. PMID[http://www.ncbi.nlm.nih.gov/pubmed/16603623 16603623]</ref> | ||
</ref> | </ref> | ||
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