User:Marvin O'Neal/VlsE

From Proteopedia

Revision as of 23:55, 29 April 2012

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. IR’s 1-5 are primarily nonantigenic in humans, while IR₂ and IR₄ exhibit antigenicity in mice. However, the 25 amino acid long IR₆ exhibits strong immunodominance in both humans and mice ^{[4] [5]}. The variable regions encompass 37% of the VlsE’s exposed surface area despite comprising only 25% of the protein ^{[6] [7]}. 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 ^[8].

Function in Immune System Evasion

VlsE is essential to the persistence and virulence of Lyme disease ^[9]. This rapid recombination event is stimulated by the host’s cytokines and absence of those cytokines results in a decreased bacterial burden ^[10]. In addition, VlsE is upregulated under humoral immune pressure ^[11]. 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. This makes it unlikely that enough of a single VR variation will be present in large enough supply to lead to an immunodominant variable region ^[12]. Thus, shielding of the immunodominant IR₆ by regions not subject to antibody response allows for IR₆ to elicit an immune response while remaining inaccessible to antibody binding ^{[13] [14] [15]}.

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 ^[16].

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 ^{[17] [18]}. 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 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 ^[19].

Additional Links

Lyme Disease Microbiology CDC Lyme Disease Page Lyme Disease Ecology, Epidemiology, and Prevention of Lyme Disease- CDC Antigenic Variation

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.