User:Marvin O'Neal/VlsE

From Proteopedia

Revision as of 20:58, 29 April 2012

Overview

VlsE is a surface lipoprotein of Borrelia burgdorferi, the causative agent of Lyme Disease. It undergoes antigenic variation ostensibly important to 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 (1,2). This model represents one of these subunits with focus on the variable domain. It contains six variable regions (VRs), highlighted in green, and six invariable regions (IR1-IR6). The invariable regions are largely embedded in the protein and remain relatively unchanged within the host and across strains. IR6, a 26 amino acid long region highlighted in red and yellow, exhibits immunodominance (5, 6). 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, in contrast, 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).

Function in Immune System Evasion

The variable regions undergo the a recombination event leading to variation with an estimated 10³⁰ possible combinations, far exceeding the number of antibodies found in the human immune system (6). This rapid recombination is initiated by the host’s cytokines, while absence of those cytokines results in a decreased bacterial burden (3). It is speculated that absence of cytokines leads to little VR variation and cytokine inhibition is proffered as a potential avenue of investigation for alternative vaccination (7). The nature of variable regions makes it unlikely that enough of a single VR variation will be present in large enough supply to lead to an immunodominant variable region (6). Thus, cytokine inhibition would in theory prevent variation, thereby creating the potential for an immunodominiant VR region. This allows for elicitation of an antibody response by the VR regions, which are exposed to antibody binding, thereby negating its shielding effect. As mentioned, shielding of the immunodominant IR6 by regions which constantly vary allows for IR6 to elicit an immune response while remaining inaccessible to antibody binding. This combined with the decreased bacterial burden observed in absence of cytokines, and presumably little VR variation, supports the speculated importance of VlsE in evasion of the immune system (2, 3, 5).

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 (4, 5). 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 for patients vaccinated against OspA. The CDC ((pdf) currently recommends a two-step test incorporating first an ELISA followed by a Western blot to eliminate false positives. Therefore, this one-step ELISA test presents an economical and more accurate improvement over the current two-step model (4).

Additional Links

Studio:G2SecL01

References

1. Liang F T and Philipp M T. 1999. Analysis of antibody response to invariable regions of VlsE, the variable surface antigen of Borrelia burgdorferi. American Society of Microbiology. 67(12): 7602-6706.
2. Eicken C, Sharma V, Klabunde T, Lawrenz M B, Hardam J M , Norris S J and Sacchettini J C. 2002. Crystal structure of Lyme disease variable surface antigen VlsE of Borrelia burgdorferi. The Journal of Biological Chemistry. 277(24): 21691-29696.
3. Anguita J, Thomas V, Samanta S, Persinski R, Hernanz C, Barthold S W and Fikrig E. 2001. Borrelia burgdorferi-induced inflammation facilitates spirochete adaptation and variable major protein-like sequence locus recombination. The American Association of Immunologists. 167: 3383-3390.
4. Liang F T, Steere A C, Marques A R, Johnson B J B, Miller J N and Philipp M T. 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.
5. Liang FT and Philipp MT. 2000. Epitope mapping of the immunodominant invariable region of Borrelia burgdorferi VlsE in three host species. American Society of Microbiology. 68(4): 2349-2352.
6. Liang FT, Alvarez AL, Gu Y, Nowling JM, Ramamoorthy R and Philipp MT. 1999. An immunodominant conserved region within the variable domain of VlsE, the variable surface of Borrelia burgdorferi. The American Association of Immunologists. 163: 5566-5573.
7. Schuijt T J, Hovius J W, van der Poll T, van Dam A P, Fikrig E. January 2011. Lyme borreliosis vaccination: the facts, the challenges, the future. Trends in Parasitology. 27(1): 40-47.