Conclusions and Proposals for Future Work

Conclusions and Proposals for Future Work

Lyme disease has been very thoroughly studied since its discovery in 1982, but is still a rather new disease. There are still plenty of areas where our knowledge can be expanded regarding Lyme disease. Not very much is known about the enzymatic mechanisms of the proteins produced by the spirochete. This may be due to the fact that most are found in the outer membrane of the bacteria and are difficult to isolate for structural and mechanistic studies. Diagnosis methods can still be improved upon and treatment options must also be expanded upon, especially for those patients who continue to have symptoms after antibiotic treatment.

 

Three possible proposals for future work are as follows:

1. Because the crystal structure of OspE in complex with factor H has recently be obtained, more work must be done to further understand what residues are crucial to the protein function and factor H binding. The need for a Lyme disease vaccination makes this protein of great interest. Future work must be done to determine what kinds of small biomolecules may best inhibit the protein. An inhibitor of OspE would be useful in that it would prevent OspE from binding factor H and bypassing the complement immune system response. The C3b protein would stay bound to the bacterial surface allowing the pathogen to be taken up and degraded by macrophages.

The active site of OspE bound to factor H using PDB viewer. Future studies on the active site of this protein may lead to a possible vaccine or other treatment options.
The active site of OspE bound to factor H using PDB viewer. Lys43, Arg66, Glu68, and Arg1182 of OspE appear to be important to the binding of FH, due to the apparent hydrogen bonds make between them and FH. Future studies on the active site of this protein may lead to a possible vaccine or other treatment options.

2. In general, more structural experiments must be done. One that may be useful is determining the crystal structure of the fibronectin-binding protein (BBK32). B. burgdorferi are capable of binding to fibronectin in the extracellular matrix of host cells. This allows them to congregate in areas of the body such as joints, the nervous system, and the heart. The congregation of the bacteria may make it difficult for the body’s immune system to thoroughly fight of infection in these areas. If a crystal structure of the fibronectin-binding protein can be obtained, a better understanding of the protein’s active, or binding, site and how it binds to fibronectin can be gained. Learning this information can help to create an inhibitor of the protein leading to an increase of circulating bacteria, which will be easier to attack by the immune system.

The spirochete bacteria binds to decorin and fibronectin using the outer surface decorin and fibronectin binding proteins.
The spirochete bacteria binds to decorin and fibronectin using the outer surface decorin and fibronectin binding proteins. This leads to a build up of bacteria in the joints, making it difficult to fight off the infection. An inflammatory response often leads to arthritis. Steere et al. 2004

3. A better understanding of the symptoms of post-Lyme disease patients must also be gained in order to better help those who cannot seem to get rid of the disease. The study done in the Chandra et al. (2011) paper showed that post-Lyme disease patients have a strong antibody response to specific invariable domains of VlsE not seen in early lyme disease patients. Unfortunately, this study only tested the antibody response to a single sequence variation of the VlsE protein and likely missed other target epitopes in the protein’s variable domain. Therefore, this study must be continued. Finding more  target epitopes of the variable VlsE proteins will help with creating new tests to detect Lyme disease in post-Lyme patients and may also help in creating possible treatments for the disease during this state as well.