User:Marvin O'Neal/OspA: Difference between revisions
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It is not fully understood how <i>Borrelia</i> get past the [http://en.wikipedia.org/wiki/Blood-brain_barrier blood-brain barrier], though some researchers suggest a paracellular route, which involves a process using transient tether-type associations, short-term dragging interactions, and stationary adhesion. There is evidence that <i>Borrelia</i> utilizes OspA in the transient tethering stage. The blood-brain barrier is composed of brain microvascular endothelial cells, astrocytes, a basement membrane, pericytes, and neurons. OspA is a major adherent molecule to brain microvascular cells by binding to the CD40 receptors outside, which results in events that are typically seen when leukocytes cross the blood brain barrier. | It is not fully understood how <i>Borrelia</i> get past the [http://en.wikipedia.org/wiki/Blood-brain_barrier blood-brain barrier], though some researchers suggest a paracellular route, which involves a process using transient tether-type associations, short-term dragging interactions, and stationary adhesion. There is evidence that <i>Borrelia</i> utilizes OspA in the transient tethering stage. The blood-brain barrier is composed of brain microvascular endothelial cells, astrocytes, a basement membrane, pericytes, and neurons. OspA is a major adherent molecule to brain microvascular cells by binding to the CD40 receptors outside, which results in events that are typically seen when leukocytes cross the blood brain barrier. | ||
Activation of CD40 receptors leads to the production of proinflammatory cytokines and enhanced expression of ICAM-1, E-selectin and VCAM-1, resulting in increased cell binding, and the formation of fenestrations due to increased vascular endothelial growth factor, and vascular permeability factor. OspA might be mimicking leukocytes in order to cross the blood brain barrier. However not all strains of | Activation of CD40 receptors leads to the production of proinflammatory cytokines and enhanced expression of ICAM-1, E-selectin and VCAM-1, resulting in increased cell binding, and the formation of fenestrations due to increased vascular endothelial growth factor, and vascular permeability factor. OspA might be mimicking leukocytes in order to cross the blood-brain barrier. However not all strains of <i>Borrelia</i> can utilize OspA to do this, OspA only contributes about 70% to adherence, and other <i>Borrelia</i> proteins are also needed in this process. It has also been seen that OspA mediates the adhesion of <i>Borrelia</i> to murine neural and glial cell lines. <ref name="pulzova">PMID: 22355605</ref> | ||
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The membrane composition of <i>Borrelia</i> is abundant in both OspA and OspB, and the two proteins share a 53% similarity in their primary sequences. Both OspA and OspB are expressed in the tick's gut and downregulated during feeding and aid in its survivability; however, OspA is overall less varied and reactive than OspB, which has greater variability.<ref name="becker">PMID: 15713683</ref> The relatively conserved sequence of OspA thus lends itself better to study and application toward the development of a vaccine for a broader range of <i>Borrelia</i> strains in the treatment of Lyme disease than that of OspB. The first vaccine used a purified recombinant form of OspA and functioned in blocking transmission of the spirochetes expressing OspA from tick to host during feeding, killing them while still attached to the tick's gut.<ref name="connolly">PMID: 15864264</ref><ref name="battisti">PMID: 18779341</ref> The vaccine, Lymerix, had shown 76% and 92% effectiveness in separate clinical trials in which patients were treated for two years following a three-dose schedule. However, the vaccination was suspended from use in 2002 when opponents claimed the [http://en.wikipedia.org/wiki/Immunoglobulin_G IgG antibodies] for OspA were associated with the onset of severe chronic arthritis, as well as other side effects affecting immunity.<ref name="connolly">PMID: 15864264</ref><ref name="plotkin">PMID: 21217175</ref> This fact, in conjunction with the desire for a more widespread vaccine treating multiple strains of <i>Borrelia</i>, has spurred research towards a new vaccine. | The membrane composition of <i>Borrelia</i> is abundant in both OspA and OspB, and the two proteins share a 53% similarity in their primary sequences. Both OspA and OspB are expressed in the tick's gut and downregulated during feeding and aid in its survivability; however, OspA is overall less varied and reactive than OspB, which has greater variability.<ref name="becker">PMID: 15713683</ref> The relatively conserved sequence of OspA thus lends itself better to study and application toward the development of a vaccine for a broader range of <i>Borrelia</i> strains in the treatment of Lyme disease than that of OspB. The first vaccine used a purified recombinant form of OspA and functioned in blocking transmission of the spirochetes expressing OspA from tick to host during feeding, killing them while still attached to the tick's gut.<ref name="connolly">PMID: 15864264</ref><ref name="battisti">PMID: 18779341</ref> The vaccine, Lymerix, had shown 76% and 92% effectiveness in separate clinical trials in which patients were treated for two years following a three-dose schedule. However, the vaccination was suspended from use in 2002 when opponents claimed the [http://en.wikipedia.org/wiki/Immunoglobulin_G IgG antibodies] for OspA were associated with the onset of severe chronic arthritis, as well as other side effects affecting immunity.<ref name="connolly">PMID: 15864264</ref><ref name="plotkin">PMID: 21217175</ref> This fact, in conjunction with the desire for a more widespread vaccine treating multiple strains of <i>Borrelia</i>, has spurred research towards a new vaccine. | ||
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To address the concerns of vaccine with broader protection, creation of a chimera, mixing the OspA of different strains of <i>Borrelia</i> would be ideal. Study of the epitope of <scene name='Studio:G2SecL03/Ospafab-ospa/3' target="complex">OspA</scene> and its <scene name='Studio:G2SecL03/Ospafab-interaction/3' target="complex">interactions</scene> with the murine monoclonal antibody <scene name='Studio:G2SecL03/Ospafab-fab/3' target="complex">LA-2</scene> have proved useful in determining effectiveness of a given vaccine trial as high levels of antibodies in test sera compete against LA-2 for binding with OspA. LA-2 makes direct contact with three exposed loops of the C-terminus of OspA. The recognition of OspA by LA-2 requires an induced fit mechanism where these three loops undergo conformational changes to optimize their interaction in the complex. <ref name="ding">PMID: 11183781</ref> | |||
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<h3>List of Available Scenes for the OspA:LA-2 Complex</h3> | |||
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<li><scene name='Studio:G2SecL03/Ospafab-orig/3' target="complex">Reset model</scene><br><br></li> | |||
<li><scene name='Studio:G2SecL03/Ospafab-fab/3' target="complex">LA-2</scene> Fab antibody (Bluish regions indicate heavy chains (chains B & D of 1FJ1) and greenish regions indicate light chains (chains A & C of 1FJ1)</li> | |||
<li><scene name='Studio:G2SecL03/Ospafab-ospa/3' target="complex">OspA</scene> proteins in complex with the LA-2 Fab antibody</li> | |||
<li><scene name='Studio:G2SecL03/Ospafab-interaction/3' target="complex">Closeup</scene> of the antigen:antibody interactions</li> | |||
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