Outer surface protein B (OspB) of the Lyme disease spirochete bacterium

From Proteopedia

Introduction

is an outer surface protein found on the spirochete Borrelia burgdorferi, which is the causative agent of Lyme disease. The functions of OspB are not yet fully known or understood, though it has been shown to be necessary for antibody recognition as well as the ability of B. burgdorferi to infect its hosts.

Significance in Lyme Disease

​Lyme disease is an inflammatory disorder brought on by infection by the spirochete Borrelia burgdorferi. B. burgorferi can be harbored in the midgut of Ixodes dammini ticks and transmitted when an infected tick feeds on a human host (Burgdorfer et al 1982). Some evidence suggests that OspB may play a role in the ability of B. burgdorferi to adhere to the tick’s midgut; genetic  expression of OspB is down regulated while ticks are feeding, potentially facilitating movement from the vector to the host. OspB also has a highly conserved region of hydrophobic residues which could provide a binding site for a small peptide, linear saccharide or protein loop (Becker et al 2005). Antibodies that recognize B. burgdorferi generally bind to lipoproteins on their outer membranes such as OspB. Two antibodies, CB2 and , were discovered to have a bactericidal effect on B. burgdorferi even in the absence of complementary immune cells. Experiments have shown that administration of these antibodies enabled T-cell deficient mice to clear a B. burgdorferi infection, confirming that the mechanism of their bactericidal action is independent of the presence of phagocytes or complement (Connolly and Benach 2005). It is unclear how binding of H6831 or CB2 can lead directly to lysis of the bacterium. The sequence and structure of the antibodies appear typical for IgG2 heavy chain/ kappa light chain class with no features to distinguish them from antibodies that lack bactericidal action (Becker et al 2005). Given that there is no evidence that the bactericidal action is intrinsic to the antibody it could potentially be due to some feature of OspB.

Antibody Binding

​X- ray diffraction analysis of crystallized samples of both pure OspB and the revealed conformational differences between bound and unbound OspB. In the bound form, strands of a beta-sheet were disordered or removed by proteolysis and other minor conformational changes were observed. However, there were multiple variables introduced through the crystallization process, the missing strands could have been removed by a contaminating protease or autoproteolytic activity and the other minor conformational changes may have only been indirectly related to the Fab binding (Becker et al 2005). ​H6831’s epitope is located on OspB’s C-terminus (residues 152-296). H6831’s ability to bind OspB is completely dependent on the presence of a at the residue 253 position. In earlier experiments investigating a potential anti-OspB monoclonal antibody vaccine had inconsistent success because the OspB sequence is variable. The binding between OspB and H6831 revolves around the OspB Lys-253 residue. The Lys-253 becomes wedged between the and residues of the H6831 heavy chain Band forms an ion pair with the residue. Alternative strains of B. burgdorferi with non-lysine residues at the 253 position of OspB were found to have little or no H6831 binding (Becker et al).  

Discussion

​H6831 and CB2 are functionally identical, both disrupt the membrane of B. burgdorferi which leads directly to the cell’s death (LaRocca and Benach 2008).  Despite a lack of understanding of the mechanism, it is clear that H6831 and CB2’s bactericidal action in the absence of complement is a crucial factor of the immune response to a B.  burgdorferi infection. B. burgdorferi have the ability to bind complement inhibitor factor H to multiple surface proteins allowing them to avoid complement mediated lysis (Connolly and Benach 2005). B. burgdorferi can also evade the immune response through antigenic variation in their populations. Mutant forms of OspB with a truncated C-terminal, lacking epitopes for bactericidal antibodies, appear spontaneously without selection. Mutants with a truncated C-terminal or an amino acid substitution at the residue 253 position can then be enriched when they encounter the selective pressure of H6831 or CB2. These escape mutants have created strains with a Thr, Cys, Gly or Glu in place of lys 253, which are resistant to bactericidal Fabs (Becker et al 2005). ​OspB’s variable sequence makes it an ineffective target for protective monoclonal vaccines, but the direct bactericidal action of H6831 and CB2 makes them as effective as some antibiotics (Becker et al 2005). Even with increased knowledge of the nature of B. burgdorferi infections, there are often long term complications for patients who have contracted Lyme disease. The spirochetes’ ability to evade the immune response can leave behind escape mutants which remain to cause additional waves of infection. Patients occasionally experience symptoms associated with Lyme disease, such as joint inflammation, even when there is no longer evidence of an active infection. It has been suggested that autoimmunity may play a role in the pathogenesis of Lyme disease; antibodies directed against Osps, including anti-OspB antibodies, have been specifically implicated. Anti-Osp antibodies raised against B. burgdorferi will remain after the infection is cleared and they seem to have reactivity with lymphoid/ myeloid adhesion molecules which may result in the chronic joint inflammation that some patients may experience (LaRocca and Benach 2008). Bactericidal antibodies are attractive targets for potential therapeutic use, however their suitability for this purpose remains under investigation.

Related Structures

• CB2
• OspB-H6831 Complex

Links

• Lyme Disease CDC Lyme Disease Webpage
• Lyme Disease
• Antibodies
• Borrelia burgdorferi
• Ixodes Dammini

See also

Outer surface protein

References

1. Becker, M., Bunikis, J., Lade, B.D, Dunn, J.J., Barbour, A.G., Lawson, C.L. “Structural Investigation of Borrelia burgdorferi OspB, a BactericidalFab Target” The Journal of Biological Chemistry; Vol. 280, No.17, issue of April 29, pp. 17363- 17370, 2005

2. Burgdorfer, W., Barbour, A.G., Hayes, S.F., Benach, J.L., Grundwaldt, E., Davis, J.P. “Lyme Disease—A Tick-Borne Spirochetosis” Science, New Series, Vol. 216, No. 4552 (Jun. 18, 1982), pp. 1317-1319

3. LaRocca, T.J., Benach, J.L. 2008 “The Important and Diverse Roles of Antibodies in the Host Response to Borrelia Infections” Specialization and Complementation of Humoral Immune Responses to in Infection. Current Topics in Microbiology and Immunology 319

4. Connolly, S.E., Benach, J.L. “The Versatile Roles of Antibodies in Borrelia Infections” Nature Reviews: Microbiology, Volume 3, May 2005, pp. 411-420