User:Marvin O'Neal/OspA: Difference between revisions
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<h3>Migration Across the Blood-Brain Barrier</h3> | <h3>Migration Across the Blood-Brain Barrier</h3> | ||
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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 [[1aly|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 <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> | 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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<scene name='Studio:G2SecL03/Ospa-loop1/1' target="OspA-manip">Loop 1</scene>, (residues 203-220), is important in showing variation amongst the different strains of <i>Borrelia</i> as well as being optimally conformed for binding without steric hindrance. <scene name='Studio:G2SecL03/Ospa-loop2/1' target="OspA-manip">Loop 2</scene> (residues 224-233) and <scene name='Studio:G2SecL03/Ospa-loop3/1' target="OspA-manip">Loop 3</scene> (residues 246-257) are more strongly conserved than Loop 1 but also help to show some variation amongst strains. The LA-2 Fab antibody readily recognizes OspA from <i>B. burgdorferi</i>, but does not recognize that from <i>B. afzelii</i> or <i>B. garinii</i>. | <scene name='Studio:G2SecL03/Ospa-loop1/1' target="OspA-manip">Loop 1</scene>, (residues 203-220), is important in showing variation amongst the different strains of <i>Borrelia</i> as well as being optimally conformed for binding without steric hindrance. <scene name='Studio:G2SecL03/Ospa-loop2/1' target="OspA-manip">Loop 2</scene> (residues 224-233) and <scene name='Studio:G2SecL03/Ospa-loop3/1' target="OspA-manip">Loop 3</scene> (residues 246-257) are more strongly conserved than Loop 1 but also help to show some variation amongst strains. The LA-2 Fab antibody readily recognizes OspA from <i>B. burgdorferi</i>, but does not recognize that from <i>B. afzelii</i> or <i>B. garinii</i>. | ||
Between <i>B. burgdorferi</i> and <i>B. afzelii</i> genetic sequences are generally invariant, but two residues change between the species: <scene name='Studio:G2SecL03/Ospa-ala208/1' target="OspA-manip">Alanine (Ala) 208</scene> in <i>B. burgdorferi</i> is a Glutamine (Gln) in <i>B. afzelii</i>, and <scene name='Studio:G2SecL03/Ospa-asn251/1' target="OspA-manip">Asparagine (Asn) 251</scene> in <i>B. burgdorferi</i> is an Alanine (Ala) in <i>B. afzelii</i>. <i>B. garinii</i> has more variation and in addition to the previous two differences, having at least one more difference, where <scene name='Studio:G2SecL03/Ospa-ala215/1' target="OspA-manip">Alanine (Ala) 215</scene> in <i>B. burgdorferi</i> is a Lysine (Lys), and sometimes also has a deletion at <i>B. burgdorferi</i>’s Alanine 208. LA-2 and OspA of <i>B. burgdorferi</i> form a tight interface when binding, and the longer Glutamine (Gln) sidechain found in <i>B. afzelii</i> and <i>B. garinii</i> is more difficult to accommodate, causing less binding. A chimera that was weakly recognized by LA-2 was made with parts of loop 1 from <i>B. burgdorferi</i>, and loops 2 and 3 from <i>B. garinii</i>.<ref name="ding">PMID: 11183781</ref> Recently, a different kind of chimera has been made which combined the proximal region of <i>B. burgdorferi</i> and distal region of <i>B. afzelii</i>, and was able to successfully protect mice from both species. | Between <i>B. burgdorferi</i> and <i>B. afzelii</i> genetic sequences are generally invariant, but two residues change between the species: <scene name='Studio:G2SecL03/Ospa-ala208/1' target="OspA-manip">Alanine (Ala) 208</scene> in <i>B. burgdorferi</i> is a Glutamine (Gln) in <i>B. afzelii</i>, and <scene name='Studio:G2SecL03/Ospa-asn251/1' target="OspA-manip">Asparagine (Asn) 251</scene> in <i>B. burgdorferi</i> is an Alanine (Ala) in <i>B. afzelii</i>. <i>B. garinii</i> has more variation and in addition to the previous two differences, having at least one more difference, where <scene name='Studio:G2SecL03/Ospa-ala215/1' target="OspA-manip">Alanine (Ala) 215</scene> in <i>B. burgdorferi</i> is a Lysine (Lys), and sometimes also has a deletion at <i>B. burgdorferi</i>’s Alanine 208. LA-2 and OspA of <i>B. burgdorferi</i> form a tight interface when binding, and the longer Glutamine (Gln) sidechain found in <i>B. afzelii</i> and <i>B. garinii</i> is more difficult to accommodate, causing less binding. A chimera that was weakly recognized by LA-2 was made with parts of loop 1 from <i>B. burgdorferi</i>, and loops 2 and 3 from <i>B. garinii</i>.<ref name="ding">PMID: 11183781</ref> Recently, a different kind of chimera has been made which combined the proximal region of <i>B. burgdorferi</i> and distal region of <i>B. afzelii</i>, and was able to successfully protect mice from both species.<ref name="livey">PMID: 21217174</ref> | ||
</p> | </p> | ||
