User:Marvin O'Neal/Antibody OspA and OspB
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===''Borrelia burgdoferi''=== | ===''Borrelia burgdoferi''=== | ||
| - | The causative agent of [http://en.wikipedia.org/wiki/Lyme_disease Lyme disease] is ''[http://en.wikipedia.org/wiki/Borrelia_burgdorferi Borellia burgdorferi]'', a [http://en.wikipedia.org/wiki/Spirochaete spirochaete] found in the gut of hard bodied ticks of genus ''[http://en.wikipedia.org/wiki/ Ixodes]''. A factor contributing to the severity of Lyme disease is its resistance to certain forms of complement-dependent immune response by the evasion of the alternative complement pathway | + | The causative agent of [http://en.wikipedia.org/wiki/Lyme_disease Lyme disease] is ''[http://en.wikipedia.org/wiki/Borrelia_burgdorferi Borellia burgdorferi]'', a [http://en.wikipedia.org/wiki/Spirochaete spirochaete] found in the gut of hard bodied ticks of genus ''[http://en.wikipedia.org/wiki/ Ixodes]''. A factor contributing to the severity of Lyme disease is its resistance to certain forms of complement-dependent immune response by the evasion of the [http://en.wikipedia.org/wiki/Alternative_complement_pathway alternative complement pathway] and the blocking of complement [http://en.wikipedia.org/wiki/Complement_component_3 C3].<ref>PMID:18080415</ref> This resistance increases the importance of the complement independent immune response when combating ''B. burgdorferi''. Certain fragment antigen binding regions ([http://en.wikipedia.org/wiki/Fragment_antigen-binding fab]) of IgG and IgM monoclonal antibodies (mAbs) are bactericidal even in the absence of complement. Binding of these fabs to their corresponding outer surface protein (OspA and OspB) of ''B. burgdoferi'' leads to the lysis of the bacteria.<ref>PMID:15864264</ref> |
| - | ===Fragment Antigen Binding (fab) | + | ===Fragment Antigen Binding (fab)=== |
[[Image:Fab reigon.png|right|thumb|Digestion of an antibody by Papain separates the fab reigons from the antibody]] | [[Image:Fab reigon.png|right|thumb|Digestion of an antibody by Papain separates the fab reigons from the antibody]] | ||
| - | + | Fab consists of a [http://en.wikipedia.org/wiki/Immunoglobulin_heavy_chain heavy chain] and [http://en.wikipedia.org/wiki/Immunoglobulin_light_chain light chain] and each chain is composed of a variable and a constant region. The [http://en.wikipedia.org/wiki/Paratope paratope] is located in the N terminal of the variable region of the heavy and light chains of the fab. H6831 and CB2 are IgG mAbs that targets the C-terminal of OspB and LA-2 is an IgM mAb that targets the C-terminal of OspA.<ref>PMID:107164</ref> | |
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| - | ==OspB and H6831== | ||
| - | <Structure load='1RJL' size='300' frame='true' align='right' caption='OspB and H6831 Fab complex' scene='Studio:G1SecL01/1/10' /> | ||
| - | <scene name='Studio:G1SecL01/1/10'>Restore Original Scene</scene> | ||
| - | ===Complex Interaction between OspB and H6831=== | ||
| - | Fab-Osp complexes, such as the OspB-H6831 complex, consist of two main components; the <scene name='Studio:G1SecL01/1/11'>outer surface protein</scene> (OspB in this case), and the <scene name='Studio:G1SecL01/1/12'>fab</scene>, which is subdivided into the <scene name='Studio:G1SecL01/1/14'>heavy chain</scene>, and the <scene name='Studio:G1SecL01/1/13'>light chain</scene>. Most hydrogen bonds and electrostatic interactions that are responsible for the binding of H6831 to OspB are between the three adjacent surface-exposed <scene name='Studio:G1SecL01/1/15'>loops</scene> at the C-terminal of OspB and some <scene name='Studio:G1SecL01/1/16'>residues</scene> on the fab heavy chain that include tyrosine, tryptophan, glutamate, and histidine. The majority of the electrostatic and hydrogen-bonded interactions are between loop 2 (residues 250-254) and the fab heavy chain. <scene name='Studio:G1SecL01/1/17'>Lysine 253</scene> in loop 2 of OspB has a necessary and major role due to its central position in the exposed loops. A mutation at its position abrogates the binding interaction and causes the resistance of the bacteria to the bactericidal effect of the fab. Lys 253 binds to the two aromatic residues on the fab heavy chain, tyrosine (green link) and tryptophan (green link). It also makes hydrogen bonds with the glutamate (green link) in the heavy chain of the fab and forms an ionic bond. Carbonyl in loop 1 (green link) of the OspB interacts with histidine in the fab heavy chain. <scene name='Studio:G1SecL01/1/18'>Loop 3</scene> of OspB interacts with fab light chain. <ref>Becker; Bunikis et al. 2004</ref>. | ||
| - | ===Conformational Changes to OspB=== | ||
| - | The binding leads to some conformational changes in OspB. Whereas Ding et al.<ref>Ding et al</ref> found no changes in the C-terminal of OspA upon the binding to the fab. The most significant difference between the free and the complexed structure of OspB is the loss of the central <scene name='Studio:G1SecL01/1/19'>beta sheet</scene> strands 1-4. Both small positional shifts near the Fab binding site and a few larger structural changes away from the binding site were observed. The largest shifts (7– 8 Å) correspond to the repositioning of a loop opposite the Fab-binding site (residues 218 –220). In the free OspB structure, all regions that exhibit shifts are adjacent to the central sheet; in the OspB-H6831 complex they all shift toward, and slightly overlap, the position of the missing sheet. These observations suggest that the larger conformational changes are related to the loss of the central sheet, which could have happened through proteolytic cleavage or fortuitous crystal contacts <ref>Becker; Bunikis et al. 2004</ref> | ||
| - | |||
| - | ====Requirements for the Bactericidal Effect and Proposed Mechanism==== | ||
| - | The fab binding destabilizes the outer membrane (OM) of B. burdorferi, with subsequent formation of spheroplasts. It has been observed that the bactericidal action, but not the binding, requires the presence of bivalent cations (Mg2+ and Ca2+). Escudero et al. study demonstrated the inability of fab to kill bacteria in the absence of the bivalent cations. It was speculated that OspB- Cb2 (a fab similar to H6831) complexes could create physical openings in the OM allowing for rapid infusion of electrolytes, increasing the osmolarity of the periplasm and triggering bivalent cation dependent cascades <ref>Escudero; Halluska et al. 1997</ref>. | ||
| - | Need to be rephrased and squeezed and may be a sentence about the cholestrol needs to be added and if there is a specific function for the charge triad it may be added | ||
| - | |||
| - | |||
| - | |||
| - | ==OspA and LA-2== | ||
| - | <Structure load='1FJ1' size='300' frame='true' align='right' caption='OspA-LA2 Complex' scene='Insert optional scene name here' /> | ||
| Line 39: | Line 23: | ||
| + | ==OspB and H6831== | ||
| + | <table width='500' align='right' cellpadding='5'><tr><td rowspan='2'> </td><td bgcolor='#eeeeee'><Structure load='1RJL' size='400' frame='true' align='center' scene='Studio:G1SecL01/1/10' /></td></tr><tr><td bgcolor='#eeeeee'><center>'''OspB-H6831 Complex''' (<scene name='Studio:G1SecL01/1/10'>Initial Scene</scene>)<br> | ||
| + | <scene name='Studio:G1SecL01/1/11'>OspB</scene>''':''' <scene name='Studio:G1SecL01/1/31'>Loop 1</scene> <scene name='Studio:G1SecL01/1/32'>(w/ His 52)</scene> ·· <scene name='Studio:G1SecL01/1/33'>Loop 2</scene> ·· <scene name='Studio:G1SecL01/1/34'>Lysine 253</scene> <scene name='Studio:G1SecL01/1/35'>(CPK coloring)</scene> ·· <scene name='Studio:G1SecL01/1/36'>Loop 3</scene> <br> | ||
| + | <scene name='Studio:G1SecL01/1/12'>H6831</scene>''': ''' | ||
| + | <scene name='Studio:G1SecL01/1/14'>Heavy Chain</scene> ·· <scene name='Studio:G1SecL01/1/13'>Light Chain</scene> ·· <scene name='Studio:G1SecL01/1/37'>Tyr-Trp-Glu-His</scene> <br> <scene name='Studio:G1SecL01/1/30'>OspB-H6831 Complex</scene>''': ''' <scene name='Studio:G1SecL01/1/38'>Residues 218-220</scene><br> | ||
| + | <scene name='Studio:G1SecL01/3/2'>OspB Unbound</scene>''':''' <scene name='Studio:G1SecL01/3/3'> Central β Sheet Strands 1-4 </scene> | ||
| + | </center></td></tr></table> | ||
| + | ===Interaction between OspB and H6831=== | ||
| + | <scene name='Studio:G1SecL01/1/10'>Restore Original Scene</scene> | ||
| + | The <scene name='Studio:G1SecL01/1/30'>OspB-H6831 complex</scene> consist of two components, the outer surface protein <scene name='Studio:G1SecL01/1/11'>OspB</scene> and the <scene name='Studio:G1SecL01/1/12'>fab</scene>, which is subdivided into the <scene name='Studio:G1SecL01/1/14'>heavy chain</scene> and the <scene name='Studio:G1SecL01/1/13'>light chain</scene>. Most hydrogen bonds and electrostatic interactions that are responsible for the binding of H6831 to OspB are between the <scene name='Studio:G1SecL01/1/15'>three adjacent surface-exposed loops</scene> at the C-terminal of OspB and some <scene name='Studio:G1SecL01/1/37'>residues on the fab heavy chain</scene> that include tyrosine, tryptophan, glutamate, and histidine.<ref name=becker>PMID:15713683</ref> | ||
| + | |||
| + | The majority of hydrogen bonds and electrostatic interactions are between <scene name='Studio:G1SecL01/1/33'>Loop2</scene> (residues 250-254) and the fab heavy chain. <scene name='Studio:G1SecL01/1/34'>Lys 253</scene> in loop 2 of OspB has a necessary and major role due to its central position in the exposed loops. A mutation at its position abrogates the binding interaction and causes the resistance of the bacteria to the bactericidal effect of the fab. Lys 253 interacts with the two aromatic residues on the fab heavy chain, tyrosine and tryptophan. It also makes hydrogen bonds with the glutamate 50 in the heavy chain of the fab and forms an ionic bond. Carbonyl in <scene name='Studio:G1SecL01/1/31'>loop 1</scene> of the OspB interacts with <scene name='Studio:G1SecL01/1/32'>histidine 52</scene> in the fab heavy chain. <scene name='Studio:G1SecL01/1/36'>Loop 3</scene> of OspB interacts with fab light chain.<ref name=becker /> | ||
| + | ===Structural changes to OspB in the complexed form=== | ||
| + | The binding of H6831 to OspB leads to some conformational changes in OspB compared to its <scene name='Studio:G1SecL01/3/2'> unbound form </scene>. [http://en.wikipedia.org/wiki/Crystallography Crystallography] has shown that the most significant difference is the loss of the <scene name='Studio:G1SecL01/3/3'>central β sheet strands 1-4 </scene>.<ref name=becker /> The loss of these β sheets may be due to conformational change as a result of the binding or a disorder that could have occurred during a crystallization of the complex. Both small positional shifts near the fab binding site and a few larger structural changes away from the binding site were observed. The largest shifts (7– 8 Å) correspond to the repositioning of a loop opposite the fab-binding site <scene name='Studio:G1SecL01/1/38'>at residues 218-220</scene>. In the free OspB structure, all regions that exhibit shifts are adjacent to the central sheet; in the OspB-H6831 complex they all shift toward, and slightly overlap the position of the missing sheet. | ||
| + | ===Bactericidal action=== | ||
| + | The fab binding destabilizes the [http://en.wikipedia.org/wiki/Bacterial_outer_membrane outer membrane] (OM) of B. burdorferi, with subsequent formation of [http://en.wikipedia.org/wiki/Spheroplast spheroplasts]. It has been observed that the bactericidal action, but not the binding, requires the presence of divalent cations (Mg<sup>2+</sup> and Ca<sup>2+</sup>), and | ||
| + | fab is unable to clear bacteria in the absence of these cations.<ref name=ding /> It is speculated that OspB-Cb2 (a fab similar to H6831) complexes could lead to the lysis of the cell by creating physical openings in the OM, allowing for rapid infusion of electrolytes and increasing the [http://en.wikipedia.org/wiki/Osmolarity osmolarity] of the [http://en.wikipedia.org/wiki/Periplasm periplasm].<ref>PMID:9125579</ref> | ||
| + | ==OspA and LA-2== | ||
| + | <table width='500' align='right' cellpadding='5'><tr><td rowspan='2'> </td><td bgcolor='#eeeeee'><Structure load='1FJ1' size='400' frame='true' align='center' scene='Studio:G1SecL01/2/1' /> | ||
| + | </td></tr><tr><td bgcolor='#eeeeee'><center>'''OspA-LA2 Complex''' (<scene name='Studio:G1SecL01/2/1'>Initial Scene</scene>)<br> | ||
| + | <scene name='Studio:G1SecL01/2/1'>OspA-LA2 Complex</scene>''':''' <scene name='Studio:G1SecL01/2/2'>Three Loops</scene> '''··''' <scene name='Studio:G1SecL01/2/3'>Ser 206</scene> | ||
| + | </center></td></tr></table> | ||
| + | ===OspA=== | ||
| + | <scene name='Studio:G1SecL01/2/1'>Restore Original Scene</scene> | ||
| + | OspA is usually undetectable in the early stages of Lyme disease, and is down regulated when OspC is expressed.<ref name=ospc>PMID:11230121</ref> OspA is 53% similar to OspB. Despite their similarity, OspB is susceptible to cleavage by exogenous [http://en.wikipedia.org/wiki/Protease proteases] both ''in vivo'' and ''in vitro'', whereas OspA is relatively resistant in both cases.<ref name=becker /> | ||
| + | ===Interaction between OspA and LA-2=== | ||
| + | LA-2 is an IgM murine monoclonal antibody that interacts with <scene name='Studio:G1SecL01/2/2'> three exposed loops </scene> on the C-terminal of OspA. These interactions include eight direct [[hydrogen bonds]], four solvent-bridged hydrogen bonds, three ion pairs, and numerous van der Waals interactions.<ref name=ding /> | ||
| + | ===Structural changes to OspA in the complexed form=== | ||
| + | Conformational changes upon the binding of OspA and LA-2 show that LA-2 recognition of OspA involves an induced fit mechanism where the conformations of loops 1-3 shift to optimize complementarity to the antigen-combining site.<ref name=ding /> The overall structure of the C-terminal of OspA is unchanged upon the binding of LA-2 with comparison to the free OspA. The maximum atomic shift is 4.7Å at the site of <scene name='Studio:G1SecL01/2/3'>Ser 206</scene>.<ref name=ding>PMID: 11183781</ref> | ||
| - | ==Temporary Stuff== | ||
| - | <scene name='Studio:G1SecL01/Complex_s/1'>original scene S</scene> | ||
| - | <scene name='Studio:G1SecL01/Loop_2_s/1'>Loop 2 S</scene> | ||
| - | <scene name='Studio:G1SecL01/Lys_253_s/1'>lys 253 S</scene> | ||
| - | IgG antibody fabs CB2 and <scene name='Studio:G1SecL01/1/9'>H6831</scene>are structurally similar and both target the C-terminal of <scene name='Studio:G1SecL01/1/2'>OspB</scene>. H6831 consists of a <scene name='Studio:G1SecL01/1/3'>light</scene> and a <scene name='Studio:G1SecL01/1/4'>heavy</scene> chain and each chain is composed of a variable and a constant domain. The paratope is located at the N terminal of the variable region of both the heavy and the light chains (Putnam 1979). Fab binding destabilizes the outer membrane (OM) of ''B. burdorferi'' with subsequent formation of spheroplasts. It has been observed that the bactericidal action upon binding requires the presence of bivalent cations (Mg2+ and Ca2+). When a similar fab, CB2, is bound to OspB, channels open in the OM allowing rapid infusion of electrolytes,increasing the osmolarity of the periplasm and triggering bivalent cation dependent cascades <ref>PMID:9125579</ref> | ||
| - | ##When bound to a similar fab CB2, OspB-CB2 complexes could create physical openings in the OM allowing for rapid infusion of electrolytes, increasing the osmolarity of the periplasm and triggering bivalent cation dependent cascades <ref>Escudero; Halluska et al. 1997</ref>## | ||
| + | ==Medical Application== | ||
| + | ''B. burgdoferi'' is able to escape human immune response because the outer surface proteins, to which the immune system responds, are variable. The effectiveness of different Osp molecules as [http://en.wikipedia.org/wiki/Vaccine vaccines] can vary depending on their variability. OspC and OspB are highly polymorphic, with variability of OspC observed between strains collected from within a single geographical area.<ref name=ospc /> Observed variations of OspB in ''B. burgdoferi'' (including its absence from the bacteria) are not accounted for by major [http://en.wikipedia.org/wiki/Dna DNA] arrangements or failure in [http://en.wikipedia.org/wiki/Transcription_(genetics) transcription] of the OspB gene. This indicates that the OspB gene may code for a variety of proteins, making OspB a poor candidate for use in vaccines.<ref>PMID:2668185</ref> OspA is the most conserved; of the three exposed loops, only loop 1 is variable while loops 2 and 3 are conserved. This makes OspA a more consistent antigen (compared to OspB and OspC) for the immune system to target and usable as a vaccine to Lyme disease.<ref name=ding /> | ||
| - | <scene name='Studio:G1SecL01/1/5'>three exposed loops</scene> | ||
| - | <scene name='Studio:G1SecL01/1/6'>Lysine 253</scene> | ||
| - | <scene name='Studio:G1SecL01/1/7'>Lysine 253 with crucial heavy chain amino acids</scene> | ||
| - | <scene name='Studio:G1SecL01/1/8'>B sheet that gets removed</scene> | ||
Current revision
Contents |
Introduction
Borrelia burgdoferi
The causative agent of Lyme disease is Borellia burgdorferi, a spirochaete found in the gut of hard bodied ticks of genus Ixodes. A factor contributing to the severity of Lyme disease is its resistance to certain forms of complement-dependent immune response by the evasion of the alternative complement pathway and the blocking of complement C3.[1] This resistance increases the importance of the complement independent immune response when combating B. burgdorferi. Certain fragment antigen binding regions (fab) of IgG and IgM monoclonal antibodies (mAbs) are bactericidal even in the absence of complement. Binding of these fabs to their corresponding outer surface protein (OspA and OspB) of B. burgdoferi leads to the lysis of the bacteria.[2]
Fragment Antigen Binding (fab)
Fab consists of a heavy chain and light chain and each chain is composed of a variable and a constant region. The paratope is located in the N terminal of the variable region of the heavy and light chains of the fab. H6831 and CB2 are IgG mAbs that targets the C-terminal of OspB and LA-2 is an IgM mAb that targets the C-terminal of OspA.[3]
OspB and H6831
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: ·· ·· ·· |
Interaction between OspB and H6831
The consist of two components, the outer surface protein and the , which is subdivided into the and the . Most hydrogen bonds and electrostatic interactions that are responsible for the binding of H6831 to OspB are between the at the C-terminal of OspB and some that include tyrosine, tryptophan, glutamate, and histidine.[4]
The majority of hydrogen bonds and electrostatic interactions are between (residues 250-254) and the fab heavy chain. in loop 2 of OspB has a necessary and major role due to its central position in the exposed loops. A mutation at its position abrogates the binding interaction and causes the resistance of the bacteria to the bactericidal effect of the fab. Lys 253 interacts with the two aromatic residues on the fab heavy chain, tyrosine and tryptophan. It also makes hydrogen bonds with the glutamate 50 in the heavy chain of the fab and forms an ionic bond. Carbonyl in of the OspB interacts with in the fab heavy chain. of OspB interacts with fab light chain.[4]
Structural changes to OspB in the complexed form
The binding of H6831 to OspB leads to some conformational changes in OspB compared to its . Crystallography has shown that the most significant difference is the loss of the .[4] The loss of these β sheets may be due to conformational change as a result of the binding or a disorder that could have occurred during a crystallization of the complex. Both small positional shifts near the fab binding site and a few larger structural changes away from the binding site were observed. The largest shifts (7– 8 Å) correspond to the repositioning of a loop opposite the fab-binding site . In the free OspB structure, all regions that exhibit shifts are adjacent to the central sheet; in the OspB-H6831 complex they all shift toward, and slightly overlap the position of the missing sheet.
Bactericidal action
The fab binding destabilizes the outer membrane (OM) of B. burdorferi, with subsequent formation of spheroplasts. It has been observed that the bactericidal action, but not the binding, requires the presence of divalent cations (Mg2+ and Ca2+), and fab is unable to clear bacteria in the absence of these cations.[5] It is speculated that OspB-Cb2 (a fab similar to H6831) complexes could lead to the lysis of the cell by creating physical openings in the OM, allowing for rapid infusion of electrolytes and increasing the osmolarity of the periplasm.[6]
OspA and LA-2
| |||||||
: ·· |
OspA
OspA is usually undetectable in the early stages of Lyme disease, and is down regulated when OspC is expressed.[7] OspA is 53% similar to OspB. Despite their similarity, OspB is susceptible to cleavage by exogenous proteases both in vivo and in vitro, whereas OspA is relatively resistant in both cases.[4]
Interaction between OspA and LA-2
LA-2 is an IgM murine monoclonal antibody that interacts with on the C-terminal of OspA. These interactions include eight direct hydrogen bonds, four solvent-bridged hydrogen bonds, three ion pairs, and numerous van der Waals interactions.[5]
Structural changes to OspA in the complexed form
Conformational changes upon the binding of OspA and LA-2 show that LA-2 recognition of OspA involves an induced fit mechanism where the conformations of loops 1-3 shift to optimize complementarity to the antigen-combining site.[5] The overall structure of the C-terminal of OspA is unchanged upon the binding of LA-2 with comparison to the free OspA. The maximum atomic shift is 4.7Å at the site of .[5]
Medical Application
B. burgdoferi is able to escape human immune response because the outer surface proteins, to which the immune system responds, are variable. The effectiveness of different Osp molecules as vaccines can vary depending on their variability. OspC and OspB are highly polymorphic, with variability of OspC observed between strains collected from within a single geographical area.[7] Observed variations of OspB in B. burgdoferi (including its absence from the bacteria) are not accounted for by major DNA arrangements or failure in transcription of the OspB gene. This indicates that the OspB gene may code for a variety of proteins, making OspB a poor candidate for use in vaccines.[8] OspA is the most conserved; of the three exposed loops, only loop 1 is variable while loops 2 and 3 are conserved. This makes OspA a more consistent antigen (compared to OspB and OspC) for the immune system to target and usable as a vaccine to Lyme disease.[5]
- ↑ LaRocca TJ, Benach JL. The important and diverse roles of antibodies in the host response to Borrelia infections. Curr Top Microbiol Immunol. 2008;319:63-103. PMID:18080415
- ↑ Connolly SE, Benach JL. The versatile roles of antibodies in Borrelia infections. Nat Rev Microbiol. 2005 May;3(5):411-20. PMID:15864264 doi:10.1038/nrmicro1149
- ↑ Putnam FW, Liu YS, Low TL. Primary structure of a human IgA1 immunoglobulin. IV. Streptococcal IgA1 protease, digestion, Fab and Fc fragments, and the complete amino acid sequence of the alpha 1 heavy chain. J Biol Chem. 1979 Apr 25;254(8):2865-74. PMID:107164
- ↑ 4.0 4.1 4.2 4.3 Becker M, Bunikis J, Lade BD, Dunn JJ, Barbour AG, Lawson CL. Structural investigation of Borrelia burgdorferi OspB, a bactericidal Fab target. J Biol Chem. 2005 Apr 29;280(17):17363-70. Epub 2005 Feb 15. PMID:15713683 doi:10.1074/jbc.M412842200
- ↑ 5.0 5.1 5.2 5.3 5.4 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
- ↑ Escudero R, Halluska ML, Backenson PB, Coleman JL, Benach JL. Characterization of the physiological requirements for the bactericidal effects of a monoclonal antibody to OspB of Borrelia burgdorferi by confocal microscopy. Infect Immun. 1997 May;65(5):1908-15. PMID:9125579
- ↑ 7.0 7.1 Kumaran D, Eswaramoorthy S, Luft BJ, Koide S, Dunn JJ, Lawson CL, Swaminathan S. Crystal structure of outer surface protein C (OspC) from the Lyme disease spirochete, Borrelia burgdorferi. EMBO J. 2001 Mar 1;20(5):971-8. PMID:11230121 doi:http://dx.doi.org/10.1093/emboj/20.5.971
- ↑ Bundoc VG, Barbour AG. Clonal polymorphisms of outer membrane protein OspB of Borrelia burgdorferi. Infect Immun. 1989 Sep;57(9):2733-41. PMID:2668185
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