User:Marvin O'Neal/VlsE

From Proteopedia

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Structural Overview

Variable Major Protein (VMP)-like sequence Expressed (VlsE) is a surface lipoprotein of Borrelia burgdorferi, the causative agent of Lyme Disease. It undergoes antigenic variation seemingly 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 each monomeric C & N 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, a strong antigen, 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 a sufficient amount 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 maintains 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 Trypanosoma brucei, the protozoa responsible for African sleeping sickness and Neisseria gonorrhea, the bacterial cause of 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]

C₆ Diagnostic Testing

Throughout the course of the disease, IR₆ produces a strong antibody response that can be identified from early to late phases. 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 amino acid synthetic peptide, C₆, containing 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

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