User:Marvin O'Neal/VlsE

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spinqualitylabelsall models VlsE Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Contents 1 Overview 2 Function in Immune System Evasion 3 C6 Diagnostic Testing 4 Additional Links 5 References

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 ^{[4] [5]}. 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 ^[6].

Function in Immune System Evasion

VlsE is essential to the persistence and virulence of Lyme disease ^[7]. This rapid recombination event is stimulated by the host’s cytokines and absence of those cytokines results in a decreased bacterial burden ^[8]. In addition, VlsE is upregulated under humoral immune pressure ^[9]. 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 ^[10]. 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 ^{[11] [12] [13]}.

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 ^[14].

	spinqualitylabelsall models PDB ID 1l8w.pdb Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image
	VlsE (1l8w), resolution 2.3Å (). Highlight: , , , , , , . Image:Vlse12.png

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 ^{[15] [16]}. 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 ^[17].

Additional Links

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

References