OspA L03 Group2: Difference between revisions
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<scene name='OspA_L03_Group2/Default/1'>Restore to default</scene> | <scene name='OspA_L03_Group2/Default/1'>Restore to default</scene> | ||
<Structure load='1FJ1' size='400' align='left' caption='Structure of OspA (PDB entry[[1FJ1]])' scene='OspA_L03_Group2/Default/1'> | |||
<Structure load='1FJ1' size='400' align='left' caption='Structure of OspA (PDB entry[[1FJ1]])'scene= | |||
The model presented by the Protein Data Bank is OspA containing two [http://en.wikipedia.org/wiki/Immunoglobulin_light_chain light chains] or Hybridoma Antibody LA2 (chains A and C), two [http://en.wikipedia.org/wiki/Heavy_chain heavy chains] or Hyrbridoma Antibody LA2 (chains B and D), and two outer surface protein A (chains E and F). In addition, the original PDB image suggests that the C-terminal domain was unchanged by the LA-2 binding, other than minor shifts in the conformations of all 3-loops to accommodate interactions with the Fab <ref name=Ding >PMID: 11183781</ref>. | The model presented by the Protein Data Bank is OspA containing two [http://en.wikipedia.org/wiki/Immunoglobulin_light_chain light chains] or Hybridoma Antibody LA2 (chains A and C), two [http://en.wikipedia.org/wiki/Heavy_chain heavy chains] or Hyrbridoma Antibody LA2 (chains B and D), and two outer surface protein A (chains E and F). In addition, the original PDB image suggests that the C-terminal domain was unchanged by the LA-2 binding, other than minor shifts in the conformations of all 3-loops to accommodate interactions with the Fab <ref name=Ding >PMID: 11183781</ref>. | ||
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The following is the fit mechanism where the conformations recognize LA-2 and shifts to optimize the complementary antigen combing site (Ding, 2000). There were 49 residues from the “three loops” involved that significantly affected by LA-2 binding, through findings from NMR and crystallization <ref name=Ding >PMID: 11183781</ref>. Residues 207 and 227 were excluded from analysis because of the peak overlap <ref name=Ding >PMID: 11183781</ref>. The portion of the protein chain detected through 15N-HSQC NMR that were affected by the binding of LA2 <ref name=Ding >PMID: 11183781</ref> was highlighted.<scene name='OspA_L03_Group2/Residues_203-220_loop1/2'>Residues 203 to 220 in "loop 1"</scene>” were represented by pale green, <scene name='OspA_L03_Group2/Residues_224-233_loop2/2'>residues 224-233 in loop 2</scene> were colored purple and <scene name='OspA_L03_Group2/Residues_246-257_loop3/3'>residues 247-257 in "loop 3"</scene>” were colored medium slate blue. The cool coloring of the residues shows the location of LA-2’s direct contact on the “3 loops”. Primary colors were used to represent <scene name='OspA_L03_Group2/Ala_208/4'>Ala-208</scene> as red and <scene name='OspA_L03_Group2/Ala_215/4'>Ala-215</scene> as blue in spacefills for the primary or initial identification of the LA-2 epitope on the beta-strands. The coloration of resides are all at one end, C-terminal of the isolated OspA molecule showing the side where LA-2 binds. The rest of the model were beta-sheets that were left yellow, as the neutral color, and the only alpha-helix was colored pink, to show the general overall structure of 21 anti-parrallel beta-strands to 1 alpha-helix <ref name=Ding >PMID: 11183781</ref>. | The following is the fit mechanism where the conformations recognize LA-2 and shifts to optimize the complementary antigen combing site (Ding, 2000). There were 49 residues from the “three loops” involved that significantly affected by LA-2 binding, through findings from NMR and crystallization <ref name=Ding >PMID: 11183781</ref>. Residues 207 and 227 were excluded from analysis because of the peak overlap <ref name=Ding >PMID: 11183781</ref>. The portion of the protein chain detected through 15N-HSQC NMR that were affected by the binding of LA2 <ref name=Ding >PMID: 11183781</ref> was highlighted.<scene name='OspA_L03_Group2/Residues_203-220_loop1/2'>Residues 203 to 220 in "loop 1"</scene>” were represented by pale green, <scene name='OspA_L03_Group2/Residues_224-233_loop2/2'>residues 224-233 in loop 2</scene> were colored purple and <scene name='OspA_L03_Group2/Residues_246-257_loop3/3'>residues 247-257 in "loop 3"</scene>” were colored medium slate blue. The cool coloring of the residues shows the location of LA-2’s direct contact on the “3 loops”. Primary colors were used to represent <scene name='OspA_L03_Group2/Ala_208/4'>Ala-208</scene> as red and <scene name='OspA_L03_Group2/Ala_215/4'>Ala-215</scene> as blue in spacefills for the primary or initial identification of the LA-2 epitope on the beta-strands. The coloration of resides are all at one end, C-terminal of the isolated OspA molecule showing the side where LA-2 binds. The rest of the model were beta-sheets that were left yellow, as the neutral color, and the only alpha-helix was colored pink, to show the general overall structure of 21 anti-parrallel beta-strands to 1 alpha-helix <ref name=Ding >PMID: 11183781</ref>. | ||
Revision as of 01:55, 16 August 2012
IntroductionIntroduction
Spirochetes and Lyme DiseaseSpirochetes and Lyme Disease
First recognized in 1957, Lyme disease has been estimated to affect between 20 and 100 cases per 100,000 individuals in the United States (Rupprecht, 2008). This bacterial vector of spirochetes, called Borrelia burgdorferi, was found on the gut of the Ixodes tick (Burgdorfer, 1982). The bacteria spread through the bite of the tick forming severe skin lesions. Other health complications include chronic arthritis, and neurologic and cardiac abnormalities (Burgdorferi, 1982). From 10-12 weeks of infestation, other symptoms like erythema chronicum migrans begin to appear as well(Burgdorferi, 1982). Studies were first conducted through New Zealand white rabbits (Burgdorferi, 1982) through the use of indirect immunofluorescence.
Outer surface proteinsOuter surface proteins
There are outer surface protein A, B, and C. Specifically, outer surface protein A, or OspA is found to inhibit bacterial transmission [1]. Outer surface protein A, or OspA was found to initiate an immune response that contributed towards the development of Lyme disease vaccinations. It prevented the transmission of Borrelia_burgdorferi, the causative bacterial agent of Lyme disease after the attachment of an infected tick [1].
About OspAAbout OspA
OspA is a lipoprotein found on the outer surface of the bacteria that is found to inhibit bacterial transmission [1]. In order for Lyme Disease to start and progress in the human or animal body, the initial levels of OspA is underregulated, inactivated, hidden, or OspA negative [1]. The bacteria underregulates OspA for the reason that it does not want to trigger any innate immune response from the host [1]. Experiments that showed the success of the Borrelia bacteria progressing in the body, were done through mice. Only OspA- positive borrelia admitted to apoptosis in the host; therefore, when the outer surface protein was present the Borrelia bacteria cannot survive [1]. Unless the vaccine with OspA is administered, or the bacteria has moved to a different environment of the cerebrospinal fluid or an inflammatory environment, the bacteria will activate and start to regulate OspA [1] by activating B-cells. Later this induced astrogliosis.
The whole system of OspA on the antigen interacting with the antibodies was a cascade complement system. Once the complement found OspA on borrelia, it induced an innate response of phagocytosis. Not only did OspA allowed opsonization, but also attracted leukocytes ([1].
Pathology of OspAPathology of OspA
Once entered the host through the skin or blood stream, Borrelia burgdorferi downregulated and suppressed OspA to minimize all of the host’s immunogenic characteristics [2]. When OspA on the spirochete migrated to an inflammatory environment, it induced apoptosis on the bacteria through the activation of B-cells [2]. Only OspA positive in borrelia bacteria were unable to establish an infection compared to OspA negative bacteria successfully hosted in studies of mice [2]. OspA known as a potent stimulator of neutrophils was able to kill the pathogen and attract leukocytes allowing the release of proinflammatory cytokines in a host [2] and avoid contracting Lyme disease as it affects the heart, joints, and central nervous system [2]. The reactive LA-2 antibody was found to serve as an important epitope of Osp-A binding [1] towards developing vaccinations. The free state of the 3D model exposed the C-terminal where there were 49 residues from the “three loops” involved that significantly affected by LA-2 binding, through findings from nuclear magnetic resonance, or NMR and crystallization [1].
StructureStructure
<Structure load='1FJ1' size='400' align='left' caption='Structure of OspA (PDB entry1FJ1)' scene='OspA_L03_Group2/Default/1'>
The model presented by the Protein Data Bank is OspA containing two light chains or Hybridoma Antibody LA2 (chains A and C), two heavy chains or Hyrbridoma Antibody LA2 (chains B and D), and two outer surface protein A (chains E and F). In addition, the original PDB image suggests that the C-terminal domain was unchanged by the LA-2 binding, other than minor shifts in the conformations of all 3-loops to accommodate interactions with the Fab [1].
The reactive LA-2 antibody was found to serve as an important epitope of Osp-A binding [1] towards developing vaccinations. The protein, OspA obtained from PDB was dissected to isolate and concentrate the F chain from the molecule of OspA from the crystallized structure to show the free state of the 3D model exposing the C-terminal to express the interaction with the Fab antigen combing site exposing the 3-loops where LA-2 makes direct contact [1].
The following is the fit mechanism where the conformations recognize LA-2 and shifts to optimize the complementary antigen combing site (Ding, 2000). There were 49 residues from the “three loops” involved that significantly affected by LA-2 binding, through findings from NMR and crystallization [1]. Residues 207 and 227 were excluded from analysis because of the peak overlap [1]. The portion of the protein chain detected through 15N-HSQC NMR that were affected by the binding of LA2 [1] was highlighted.” were represented by pale green, were colored purple and ” were colored medium slate blue. The cool coloring of the residues shows the location of LA-2’s direct contact on the “3 loops”. Primary colors were used to represent as red and as blue in spacefills for the primary or initial identification of the LA-2 epitope on the beta-strands. The coloration of resides are all at one end, C-terminal of the isolated OspA molecule showing the side where LA-2 binds. The rest of the model were beta-sheets that were left yellow, as the neutral color, and the only alpha-helix was colored pink, to show the general overall structure of 21 anti-parrallel beta-strands to 1 alpha-helix [1].
Vaccination (La-2)Vaccination (La-2)
OspA is the least variable protein located on the outer surface of the borrelia bacteria [1]. This results in fewer mutations to occur allowing the same vaccine to stay in use for a longer time. Individuals who were bit by an infected tick and received the ospA vaccine were able to produce anti-opsA antibodies. These antibodies enter the tick through its blood meal into the gut where spirochetes are found and are destroyed by the antibody’s detection of opsA. Therefore, before the spirochete enters the host, it will be inactivated and Lyme Disease may be prevented (Marks, 2011).
The complement system of the host also has a beneficial effect on destroying the borrelia located in the tick’s gut. It works by opsonizing these pathogens and attracting leukocytes which are a main component of the defense system against pathogens [2]. Overall, the large percentage of the antibodies raised during the OspA vaccination must bind to antigen surfaces that overlap with the LA-2 epitope [1] in order for the Borrelia bacteria to enter apoptosis.
Side EffectsSide Effects
Recent studies however have shown that neurological complications may appear in patients with this vaccination. This occurs because the down regulation of OspA from the vaccine would not be an abundant amount to activate the immune system for defense (Marks, 2011). This may then cause a wide range of adverse events such as headaches and acute neuroborreliosis(Marks, 2011).
Comparing OspA , OspB , OspCComparing OspA , OspB , OspC
References:
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 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
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 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