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==Pathogenesis of Lyme Neuroborreliosis (LNB)== | ==Pathogenesis of Lyme Neuroborreliosis (LNB)== | ||
Penetrating the immune system’s first line of defense the skin, Borrelia can cause a local infection at the site of tick attachment. These infections produce easily recognizable | Penetrating the immune system’s first line of defense the skin, Borrelia can cause a local infection at the site of tick attachment. These infections produce the easily recognizable bulls-eye rash associated with Lyme disease. While other antigens may play a greater role in the beginning of the invasion, OspA has been shown to be more active in the second stage of the infection after the bacteria spreads throughout the body. Affected areas can include the heart, joints, and the nervous system itself. The second stage is when signs of acute Lyme neuroborreliosis (LNB) begin. Symptoms of LNB include meningoradiculitis with inflammation of the nerve roots, radicular pain (Bannwarth’s syndrome), lymphocytic meningitis, in addition to cranial or peripheral neuritis.<ref name=art4>PMID:18097481</ref> | ||
=== The Elusiveness of OspA === | === The Elusiveness of OspA === | ||
Revision as of 19:08, 16 August 2012
Outer Surface Protein A (OspA) is a major lipoprotein on the borrelia burgdorferi spirochete which is a causative agent of Lyme Disease. The three loops in the C-terminus define the OspA antigen-antibody complex. The interaction between the loops and the LA-2 (antibody) forms the basis for OspA vaccination. Along with other surface proteins, OspA has many important functions that are associated with Lyme Disease such as late stage neurological disorders including acute Lyme Neuroborreliosis.
Introduction to Lyme DiseaseIntroduction to Lyme Disease
Lyme disease is the most common tick-borne disease in North American hemisphere. Responsible for transmission is a tick vector from the genus of Ixodidae. There are different bacterial strains of borrelia including B.afzellii and B.garinii being very prevalent throughout the European continent; other known strains such as B.dutonii and B. recurrentis have been discovered within the past few decades. The most common strain in the United States is borrelia burgdorgeri sensu stricto, and this treponema-like spirochete was discovered to be the causative agent of Lyme Disease discovered by Dr. Willy Burgdorferi in 1982 along with several other colleagues. [1]
Besides OspA, there are other outer surface proteins, including OspB, OspC, and Vls, which are very important for the transmission of Lyme Disease from the tick to the host, as well as establishing the infection via bloodstream disseminating throughout the host body. Early symptoms of Lyme Disease include skin lesions and rashes that have a characteristic bulls-eye appearance known as erythema chronicum migrans (ECM). It is important to note that ECM can be used for early diagnosis of Lyme Disease prior to awaiting more accurate laboratory tests. [2]
Upon infection, OspA is immediately downregulated or can even be turned off. Because of this, vaccinations for OspA are virtually ineffective once spirochetes have entered the host. Downregulation also makes OspA harder to detect; OspA is usually upregulated in the late stages of the disease and leads to more serious inflammatory disorders in the central nervous system such as acute Lyme neuroborreliosis (LNB).
Outer Surface Protein A (OspA)Outer Surface Protein A (OspA)
Structural BreakdownStructural Breakdown
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Outer Surface Protein A has approximately 270 amino acid residues. [3]In terms of secondary structure, OspA is made up of 21 anti-parallel single layer beta strands and one alpha helix. [3]OspA has three major components to its structure: an , , and a . The n-terminal is often termed as a sandwich due to its jumbled formation of amino acid residues. Most of the beta strands lie on the central sheet. Lastly, the c-terminal is called barrel domains because the three primary loops connect to both sides of the central beta sheet forming a barrel or a hole in the middle. This can be seen by rotating the molecule.
The c-terminal is heavily involved in the antigen:antibody complex unlike the n-terminal. The c-terminal houses a protruding ridge of three loops: contains residues 203-220; contains residues 224-233; contains residues 246-257. These loops define the LA-2 (antibody) epitope. More specifically, the loops indicate where the antibody binds to the antigen. This protruding ridge coupled with OspA’s elongated fold gives the surface protein a high degree of surface exposure. Loops 2 and 3 tend to be more conserved.
LA-2 RecognitionLA-2 Recognition
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Pathogenesis of Lyme Neuroborreliosis (LNB)Pathogenesis of Lyme Neuroborreliosis (LNB)
Penetrating the immune system’s first line of defense the skin, Borrelia can cause a local infection at the site of tick attachment. These infections produce the easily recognizable bulls-eye rash associated with Lyme disease. While other antigens may play a greater role in the beginning of the invasion, OspA has been shown to be more active in the second stage of the infection after the bacteria spreads throughout the body. Affected areas can include the heart, joints, and the nervous system itself. The second stage is when signs of acute Lyme neuroborreliosis (LNB) begin. Symptoms of LNB include meningoradiculitis with inflammation of the nerve roots, radicular pain (Bannwarth’s syndrome), lymphocytic meningitis, in addition to cranial or peripheral neuritis.[4]
The Elusiveness of OspAThe Elusiveness of OspA
Medical Uses or Future Direction of StudyMedical Uses or Future Direction of Study
Additional ResourcesAdditional Resources
ReferencesReferences
- ↑ Burgdorfer W, Barbour AG, Hayes SF, Benach JL, Grunwaldt E, Davis JP. Lyme disease-a tick-borne spirochetosis? Science. 1982 Jun 18;216(4552):1317-9. PMID:7043737
- ↑ Wormser GP, Dattwyler RJ, Shapiro ED, Halperin JJ, Steere AC, Klempner MS, Krause PJ, Bakken JS, Strle F, Stanek G, Bockenstedt L, Fish D, Dumler JS, Nadelman RB. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006 Nov 1;43(9):1089-134. Epub 2006 Oct 2. PMID:17029130 doi:10.1086/508667
- ↑ 3.0 3.1 Ding W, Huang X, Yang X, Dunn JJ, Luft BJ, Koide S, Lawson CL. Structural identification of a key protective B-cell epitope in Lyme disease antigen OspA. J Mol Biol. 2000 Oct 6;302(5):1153-64. PMID:11183781 doi:10.1006/jmbi.2000.4119
- ↑ 4.0 4.1 Rupprecht TA, Koedel U, Fingerle V, Pfister HW. The pathogenesis of lyme neuroborreliosis: from infection to inflammation. Mol Med. 2008 Mar-Apr;14(3-4):205-12. PMID:18097481 doi:10.2119/2007-00091.Rupprecht
- ↑ Schutzer SE, Coyle PK, Dunn JJ, Luft BJ, Brunner M. Early and specific antibody response to OspA in Lyme Disease. J Clin Invest. 1994 Jul;94(1):454-7. PMID:8040289 doi:http://dx.doi.org/10.1172/JCI117346
- ↑ Aguero-Rosenfeld ME, Roberge J, Carbonaro CA, Nowakowski J, Nadelman RB, Wormser GP. Effects of OspA vaccination on Lyme disease serologic testing. J Clin Microbiol. 1999 Nov;37(11):3718-21. PMID:10523583 doi:10.1128/JCM.37.11.3718-3721.1999