User:Marvin O'Neal/OspA: Difference between revisions
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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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<Structure load="1fj1" size="350" frame="true" align="right" name="complex" caption="Outer surface protein A (OspA) in complex with the LA-2 Fab antibody ([[1fj1|1FJ1]])."> | |||
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To address this problem of international protection it would be helpful to create a chimera, mixing the OspA of different species. In order to do this the epitope of OspA should be studied. LA-2 < | To address this problem of international protection it would be helpful to create a chimera, mixing the OspA of different species. In order to do this the epitope of OspA should be studied. <scene name='Studio:G2SecL03/Ospafab-fab/1' target="complex">LA-2</scene> is a murine monoclonal antibody that binds strongly <<SHOW INTERACTION HIGHLIGHTED (ZOOMED IN) ON 1FJ1>> to <scene name='Studio:G2SecL03/Ospafab-ospa/1' target="complex">OspA</scene>, and how effective a vaccine is correlated with LA-2 binding. 5 | ||
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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>. Between Bb. and Ba. genetic sequences are generally invariant, but two residues change between the species, ALA 208 <<ALA 208>> in Bb. is GLN in Ba., and ASN 251 <<ASN 251>> in Bb. is ALA in Ba.. Bg. has more variation and in addition to the previous two differences, has at least one more difference, where ALA 215 <<ALA 215>> in Bb. is LYS, Bg. sometimes also has a deletion at Bb.’s ALA 208. LA-2 and OspA of Bb. form a tight interface when binding, and the longer GLN sidechain found in Ba. and Bg. 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 Bb., and loops 2 and 3 from Bg. 5 Recently, a different kind of chimera has been made which combined the proximal region of Bb. and distal region of Ba., and was able to successfully protect mice from both species. 8 | <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 Bb. and Ba. genetic sequences are generally invariant, but two residues change between the species, ALA 208 <<ALA 208>> in Bb. is GLN in Ba., and ASN 251 <<ASN 251>> in Bb. is ALA in Ba.. Bg. has more variation and in addition to the previous two differences, has at least one more difference, where ALA 215 <<ALA 215>> in Bb. is LYS, Bg. sometimes also has a deletion at Bb.’s ALA 208. LA-2 and OspA of Bb. form a tight interface when binding, and the longer GLN sidechain found in Ba. and Bg. 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 Bb., and loops 2 and 3 from Bg. 5 Recently, a different kind of chimera has been made which combined the proximal region of Bb. and distal region of Ba., and was able to successfully protect mice from both species. 8 | |||
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