SB2013 L08gr01
From Proteopedia
The Importance of OspC in Lyme Disease
Lyme disease is a progressive multisystem disorder that produces a primary infection (erythema migrans), at an early stage, at the site of bite by Ixodes tick carrying spirochetes (Borrelia burgdorferi) and may spread to secondary sites (e.g. heat, nervous system, joints), if left untreated. Outer Surface Proteins (e.g. OspA, OspB and OspC) play a vital role in this infecting process. While inside the vector, presence of OspA is prominent while OspC is unexpressed on the spirochete outer membrane. When spirochetes invade the host body, OspA is suppressed and an upregulation of OspC occurs due to an induction in OspC synthesis (the surface proteins are co-regulated on the mRNA level). This upregulation of OspC occurs partially due to differential temperature change (the optimal temperature being 32-37 degrees C) in the host body. However, OspC expression decreases after 2 days (time needed for spirochete transmission) of feeding. This implies that OspC is a vital protein supporting the primary transmission of the antigen in the host body [1] .Furthermore, the tick-borne infection was shown to be prevented upon addressing active [2] or passive [3] immunization with various OspC formulations in experimental mammals. As a result, OspC is the protein of interest that is to be studied.
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OspC Structure
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| 1ggq, resolution 2.51Å () | |||||||||
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| Related: | 1f1m, 1osp, 1fj1 | ||||||||
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| Resources: | FirstGlance, OCA, RCSB, PDBsum | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
The highly variable OspC gene is located on a 27 kb circular plasmid and encodes for lipoprotein, which contains an 18 amino acid sequence. This amino acid sequence changes after processing and lipidation at the amino proximal Cys residue. The high variability of OspC gene makes OspC protein very polymorphic which varies among the major groups and even within different locations [1]. It is also important to note that there is a high variance in the amino acid sequence of the invasive from non-invasive species, contributing to the differentiation of folding and solvent structures of putative sites. The three dimensional of OspC consists of five helices and two anti-parallel beta sheets per monomer. Not all strains of OspC are invasive to humans (less than half). Even within invasive groups, the amino acid sequence varies (dissimilarity in building units), yet all of the invasive groups continue to share remarkably well reserved solvent structures within the cavity (similarity in 3D structure and folding leading to a similar function). Another point of significance to be added is that regions in all invasive species are likely to be partially occupied by heavy trace ions [1].One of the most prominent differences between OspC of invasive species and that of a non-invasive species is that OspC found on invasive strands of spirochetes has a strong negative electrostatic potential region which exists within its two-fold axis. Image 1 shows the negative electropotential region of the B31 OspC around the two fold axis in red.
Structural Function
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The importance of this negative region is immense because it is likely to have a variety of functions. Initially it has been proposed that OspC may function in the cellular adhesion of Lyme disease because of its predisposition to bind to positively charged host ligands, such as extracellular glycoproteins like fibronectin. But more recent studies have suggested that the function of OspC may be entirely different. It is now understood that OspC plays a role in immobilizing plasminogen, suggesting that OspC is a biologically relevant Plasminogen receptor on the surface of B. burgdorferi. Borrelia burgdoferi, like many bacterial pathogens, cannot produce endogenous membrane-associated proteases and has to appropriate host proteases to increase the probability of successful host colonization [4].
Immune Response
However, the existence of the negatively charged region may not be the only reason contributing the invasion. Overall structure of OspC may play an equally important role. Recent studies showed that, in serum of patients demonstrating erythema migrans (early stage of Lyme disease),IgM antibody has been found to interact with OspC [5]. On the other hand, immunoblot of serum from patients showing secondary infection has been observed to demonstrate a lower number of IgM-OspC complexes, further demonstrating the importance of OspC for the primary transmission [6]. In addition, moderate IgGreactivity to OspC has been found in the serum of patients at an early stage of Lyme disease [7]. Furthermore, supporting researches have highlighted a well-conserved immunodominant epitope located on the region of OspC demonstrating the ability of binding to antibodies [8]. IgM and IgG antibodies from serum of patients at an early stage of Lyme disease get absorbed with a carboxy-terminal (seven amino acid long) of OspC. Surprisingly, this epitope on the carboxy-terminal and its binding of antibodies is very well conserved among different invasive OspC proteins [9].
Super Vaccination
Since OspC helps with early transmission of spirochete to the host body, it will be much more efficient to develop a vaccine based on OspC compared to the current vaccination based on OspA [1]. In addition, a combinatory vaccination based on both OspA and OspC may be developed to not only produce antibody in the host body responding to OspC but also disinfecting the tick while it feeds on the host blood containing antibodies for OspA [10]. Nevertheless, due to high variance in structure (within invasive groups, which can even vary depending on location), it is a matter of difficulty to produce a globalized vaccination [1]. A globalized vaccination may work by denaturing the structure of OspC and making it impossible for it to bind is to host cells. A proposed target area for a vaccine may include areas like the well-conserved immunodominant epitope present at the carboxy-terminal of OspC [8].
References
- ↑ 1.0 1.1 1.2 1.3 1.4 Kumaran D, Eswaramoorthy S, Luft B, Koide S, Dunn J, Lawson C, Swaminathan S. 2001. Crystal structure of outer surface protein C (OspC) from the Lyme disease spirochete,Borrelia burgdorferi. The EMBO Journal: United Kingdom. Vol. 20, No. 5. 8 p.Vol. 64, No.6.5.
- ↑ Gilmore R, Kappel K, Dolan M, Burkot T, Johnson B. Outer surface protein C (OspC), but not P39, is a protective immunogen against a tick-transmitted Borrelia burgdorferi challenge: evidence for a conformational protective epitope in OspC. 1996. Infection and Immunity.
- ↑ Mbow M, Gilmore R, Titus R. An OspC-specific monoclonal antibody passively protects mice from tick-transmitted infection by Borrelia burgdorferi B31. 1999. Infection and Immunity. Vol. 67. 2 p.
- ↑ Önder O, Humphrey PT, McOmber B, Korobova F, Francella N, Greenbaum DC, Brisson D.OspC Is Potent Plasminogen Receptor on Surface of Borrelia burgdorferi. 2011.
- ↑ Wilske B, Preac-Mursic V, Schierz G, Busch K. Immunochemical and immunological analysis of European Borrelia burgdorferi strains. 1986. Zentralbl Bakteriol Mikrobiol Hyg A. Vol. 263, No. 1-2. 10 p.
- ↑ Dressler F, Whalen J, Reinhardt B, Steere A. Western blotting in the serodiagnosis of Lyme disease. 1993. J Clin Microbiol. Vol. 167. 8 p.
- ↑ Fung B, McHugh G, Leong J, Steere A. Humoral immune response to outer surface protein C of Borrelia burgdorferi in Lyme disease: role of the immunoglobulin M response in the serodiagnosis of early infection. 1994. Infection and Immunity. Vol. 62. 8 p.
- ↑ 8.0 8.1 Jobe D, Lovrich S, Schell R, Callister S. C-terminal region of outer surface protein C binds borreliacidal antibodies in sera from patients with Lyme disease. 2003. Clin Vaccine immuno.Vol. 10. 5 p.
- ↑ Lovrich S, Jobe D, Schell R, Callister S. Borreliacidal OspC antibodies specific for a highly conserved epitope are immunodominant in human Lyme disease and do not occur in mice or hamsters. 2005. Clin Vaccine Immuno. Vol. 12. 6 p.
- ↑ Greenberg, D. (2001, February 28). Brookhaven scientists determine key Lyme disease protein structure. Retrieved from http://www.bnl.gov/bnlweb/pubaf/pr/2001/bnlpr022801.htm
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