User:Marvin O'Neal/OspA

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<Structure load="1fj1" size="350" frame="true" align="right" caption="Jmol of OspA ([[1fj1]], chain F) showing secondary structures." scene="Studio:G2SecL03/Ospa_default/4"/>
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<Structure load="1fj1" size="350" frame="true" align="right" caption="Jmol of OspA ([[1fj1|1FJ1]], chain F) showing secondary structures." scene="Studio:G2SecL03/Ospa_default/4"/>
<b>OspA (Outer Surface Protein A)</b> is
<b>OspA (Outer Surface Protein A)</b> is
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][http://en.wikipedia.org/wiki/Lyme_disease|Lyme disease]], caused by the <a href="http://en.wikipedia.org/wiki/Spirochaete" alt="Spirochete">spirochete</a> <a href="http://en.wikipedia.org/wiki/Borrelia"><i>Borrelia</i></a> and spread via hard-bodied ticks belonging to the family <i>Ixodidae</i>. The Borrelia spirochetes are motile, helical organisms that contain outer surface proteins. In the U.S. it has between 20-100 cases reported per 100,000 people and the main spirochete that causes it is Borrelia burgdorferi sensu stricto (Bb.). In Europe the cases are more prevalent, causing 100-130 cases per 100,000 people, and are caused by the spirochetes Borrelia afzelii (Ba.) and Borrelia garinii (Bg.) (Connelly SE and Benach JL, 2005). Lyme disease is a debilitating disease that begins with a characteristic “Bull’s eye rash” as well as lesions throughout the body. It affects various parts of the body including the heart, joints, and both central and peripheral nervous system. Borrelia have two major outer surface proteins OspA and OspB. OspA is used to adhere to the tick gut by binding with the tick receptor TROSPA. As the tick feeds upon its host the OspA is downregulated, allowing it to enter the host (Rupprecht T, Koedel U, Fingerle V and Pfister H-W. 2008). OspA and OspB are major lipoproteins involed in Lyme disease, however OspA is the protein most related to acute Lyme neuroborreliosis (LNB), the neurological manifestation with symptoms of Meningitis as well as Cranial and Peripheral neuritis
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[http://en.wikipedia.org/wiki/Lyme_disease Lyme disease] is caused by the [http://en.wikipedia.org/wiki/Spirochaete spirochete] [http://en.wikipedia.org/wiki/Borrelia <i>Borrelia</i>] and spread via hard-bodied ticks belonging to the family [http://en.wikipedia.org/wiki/Ixodidae <i>Ixodidae</i>]. The Borrelia spirochetes are motile, helical organisms that contain outer surface proteins. In the U.S. there are between 20-100 cases of Lyme disease reported per 100,000 people and the main spirochete that causes it is Borrelia burgdorferi sensu stricto (Bb.). In Europe the cases are more prevalent, causing 100-130 cases per 100,000 people, and are caused by the spirochetes Borrelia afzelii (Ba.) and Borrelia garinii (Bg.). 1 Lyme disease is a debilitating disease that begins with a characteristic “Bull’s eye rash” as well as lesions throughout the body. It affects various parts of the body including the heart, joints, and both central and peripheral nervous system. Borrelia have two major outer surface lipoproteins involved in Lyme disease: OspA and OspB. OspA is used to adhere to the tick gut by binding with the tick receptor (TROSPA). As the tick feeds upon its host the OspA is downregulated, allowing it to enter the host. OspA is the protein most related to acute Lyme neuroborreliosis (LNB), the neurological manifestations of Lyme disease. 2
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<h2>OspA & Lyme Disease</h2>
<h2>OspA & Lyme Disease</h2>
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Acute Lyme Neuroborreliosis (LNB) is the secondary stage of Lyme disease in which the spirochete Borrelia burgdorferi invades various organs such as the heart and joints, as well as the peripheral and central nervous system (CNS). Symptoms of LNB include; Bannwarth’s Syndrome (a syndrome displayed by Central Nervous System abnormalities and neurologic signs and symptoms), Lymphocytic Meningitis (A nonbacterial meningitis with normal Cerebral Spinal Fluid glucose levels), and Cranial Neuritis (inflammation of the peripheral nervous system causing conditions such as Bell’s Palsy). OspA is involved in the inflammation and infection of the host’s body. The inflammation process is a complex one. When borrelia enter the CNS they encounter immune cells of the body such as monocytes, macrophages, and dendritic cells. These cells then release proinflammatory cytokines as well as chemokines, a type of cytokine that can signal proteins as well as induce chemotaxis and cause cells to move. An increase in these cytokines and chemokines has been seen in the CSF of patients suffering from LNB. The first step of the inflammatory response is when OspA is recognized by a monocytic cell (a type of leukocyte involved in the immune system). The monocytic cell replenishes the amount of macrophages and dendritic cells in the body and has them quicly move to inflammation signals in infected tissues. Step two of the process occcurs when the monocytic cell releases the chemokine CXCL13, a major subfamily of chemokine that is grouped depending on the arangement of its cysteine residue. In the third step of the inflammatory process, B-cells move into the CSF, responding to a few chemokines in the CXCL13 and CXCL12 families. During the next step, the B-cells are turned into plasma cells, lymphocytes that produce large quantities of antibodies. In the last step of the inflammatory response, OspA antibodies are created by upregulation in the inflammatory environment. This response is ultimately capable of killing Borrelia.
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Acute Lyme Neuroborreliosis (LNB) is part of the secondary stage of Lyme disease in which the spirochete invades peripheral and central nervous system (CNS). Symptoms of LNB include; Bannwarth’s Syndrome, Lymphocytic Meningitis, and Cranial Neuritis. OspA leads to the complex inflammation process in the brain.
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When borrelia enter the CNS they encounter immune cells of the body such as monocytes, macrophages, and dendritic cells. These cells then release proinflammatory cytokines as well as chemokines. An increase in these cytokines and chemokines has been seen in the CSF of patients suffering from LNB.
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1. The first step of the inflammatory response is when OspA is recognized by a monocytic cell.
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2. In step two the monocytic cell releases the chemokine CXCL13.
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3. In the third step of the inflammatory process, B-lymphocytes move into the CSF.
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4. During the 4th step, the B-lymphocytes are turned into plasma cells.
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5. In the 5th step antibodies are created, causing he the
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6. final step where borrelia are killed. This response can be helpful in killing borrelia but also can cause harmful inflammation. 2
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<h2>OspA Vaccination</h2>
<h2>OspA Vaccination</h2>
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Lyme disease can be prevented by avoiding areas with ticks, wearing proper attire, and using DEET (N,N-diethy-m-toluamide). However prevention by using an Osp of Borrelia could also be an effective measure. Borrelia shows abundant OspA and OspB, both of the proteins are very similar to each other; their amino acid sequences are 50% the same (Connolly, SE and Benach JL, 2005.). However OspA is more studied than OspB, and many studies related to OspA structure are developing and creating to make efficient vaccine against other lyme diseases (Battisti JM, Bono JL, Rosa PA, et al, 2008). The first vaccine against B. burgorferi sensu stricto was created targeting the OspA strain successfully (Rupprecht T, Koedel U, Fingerle V and Pfister H-W. 2008). However this vaccine is unique in that it only works while Borrelia are still in the gut expressing OspA. (Ding) The OspA vaccine, LYMErix, was discontinued in 2002 due to various weaknesses of the vaccine including its <80% efficacy, requirement for 3 doses, lack of data concerning the effects of the vaccine on children, and limitation of protection to the North American species of Borrelia. (Nigrovic and Thompson 2007). Complaints about the safety of the vaccine focused on To create a broader vaccine it would be helpful to create a chimera, using the OspA of different species. In order to do this the epitope of OspA should be studied. LA-2 is a murine monoclonal antibody that binds strongly to OspA, and how effective a vaccine is correlated with LA-2 binding. (ding)
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Lyme disease can be prevented by avoiding areas with ticks, wearing proper attire, and using DEET (N,N-diethy-m-toluamide). However prevention by using an Osp of Borrelia as a vaccine could also be an effective measure. 3 Borrelia shows abundant OspA and OspB, both of the proteins are very similar to each other; their amino acid sequences are 50% the same 1 . However OspA is more studied than OspB, and many studies related to OspA structure are developing and creating to make efficient vaccine against other Lyme diseases 4. The first vaccine against B. burgorferi sensu stricto was created targeting the OspA strain successfully 2 However this vaccine is unique in that it only works while Borrelia are still in the gut expressing OspA. (Ding) LYMErix, was discontinued in 2002 due to various weaknesses of the vaccine including its <80% efficacy, requirement for 3 doses, lack of data concerning the effects of the vaccine on children, and limitation of protection to the North American species of Borrelia. 6 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 <<SHOW FAB HIGHLIGHTED ON 1FJ1>> is a murine monoclonal antibody that binds strongly <<SHOW INTERACTION HIGHLIGHTED (ZOOMED IN) ON 1FJ1>> to OspA <<SHOW OSPA HIGHLIGHTED ON 1FJ1>>, and how effective a vaccine is correlated with LA-2 binding. 5
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<h2>Structure of OspA</h2>
<h2>Structure of OspA</h2>
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OspA is made of 21 anti-parallel β-strands and a single α-helix (Ding et al. 2000). OspA is unique due to its dumbbell shape that contains two globular domains connected by a single layer β-sheet. (Koeide) There are three loops located at the C-terminus that are important in binding, and amino acids that are unconserved between different strains. Loop 1, residues 206 and 216, has an important role in binding due to a large exposed surface area, high mobility. LA-2 recognizes OspA Bb, but does not recognize OspA from Bg.and B. afzelli Ba. which are found only in Europe and Asia. Bb. and Ba. genetic sequences are generally invariant within the species, but two residues change between the species, ALA 208 in Bb. is GLN in Ba., and ASN 251in 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 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 (Ding et al. 2000). 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.(Ding et al. 2000). 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 (Livey et al. 2011).
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OspA is made of 21 anti-parallel β-strands and a single α-helix. 5 OspA is unique due to its dumbbell shape that contains two globular domains connected by a single layer β-sheet. 7 There are three loops <<ALL 3 LOOPS> located at the C-terminus that are important in binding, and amino acids that are unconserved between different strains <<ALL 3 RESIDUES>>. Loop 1, residues 206 and 216, has an important role in binding due to a large exposed surface area, high mobility. Loop 2, residues 224-233, and Loop 3, residues 246-257, are also areas that are involved in binding. LA-2 recognizes OspA Bb, but does not recognize OspA from Bg.and Ba. Between Bb. and Ba. genetic sequences are generally invariant, but two residues change between the species, ALA 208 in Bb. is GLN in Ba., and 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 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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<h2>References</h2>
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1Connolly, SE and Benach JL. 2005. The Versatile Roles of Antibodies in Borrelia Infections. Microbiology 3: 411-420.
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2Rupprecht T, Koedel U, Fingerle V and Pfister H-W. 2008. The Pathogenesis of Lyme Neuroborreliosis: From Infection to Inflammation. Molecular Medicine 14(3-4): 205-212.
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3Nigrovic L, Thompson K. 2007. Epidemiology and Infection. The Lyme Vaccine: A Cautionary Tale. 135(1)1-8.
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4Battisti JM, Bono JL, Rosa PA, et al. 2008. Outer Surface Protein A Protects Lyme Disease Spirochetes from Acquired Host Immunity in the Tick Vector. Infect. Immun. 76(11): 5228-5237.
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5Ding W, Huang X, Yang X, Dunn J, et al. 2000. Structural Identification of a Key Protective B-Cell Epitope in Lyme Disease Antigen Osp A, Journal of Molecular Biology 302(5): 1153-1164.
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6Plotkin S. 2011. Clinical Infectious Diseases. Correcting a Public Health Fiasco: The Need for a New Vaccine Against Lyme Disease. 52(3):s721-275.
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7Koide? Who used this?
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8Livey I, O’Rourke M, Traweger A, Savidis-Dacho H, Crowe B, Barrett P, Yang X, Dunn J, Luft B. 2011. Clinical Infectious Diseases. A new approach to a Lyme Disease Vaccine. 52(3):s266-s270.
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Revision as of 02:34, 30 April 2012

Jmol of OspA (1FJ1, chain F) showing secondary structures.

Drag the structure with the mouse to rotate

OspA (Outer Surface Protein A) is

Contents

Introduction

Lyme disease is caused by the spirochete Borrelia and spread via hard-bodied ticks belonging to the family Ixodidae. The Borrelia spirochetes are motile, helical organisms that contain outer surface proteins. In the U.S. there are between 20-100 cases of Lyme disease reported per 100,000 people and the main spirochete that causes it is Borrelia burgdorferi sensu stricto (Bb.). In Europe the cases are more prevalent, causing 100-130 cases per 100,000 people, and are caused by the spirochetes Borrelia afzelii (Ba.) and Borrelia garinii (Bg.). 1 Lyme disease is a debilitating disease that begins with a characteristic “Bull’s eye rash” as well as lesions throughout the body. It affects various parts of the body including the heart, joints, and both central and peripheral nervous system. Borrelia have two major outer surface lipoproteins involved in Lyme disease: OspA and OspB. OspA is used to adhere to the tick gut by binding with the tick receptor (TROSPA). As the tick feeds upon its host the OspA is downregulated, allowing it to enter the host. OspA is the protein most related to acute Lyme neuroborreliosis (LNB), the neurological manifestations of Lyme disease. 2



OspA & Lyme Disease

Acute Lyme Neuroborreliosis (LNB) is part of the secondary stage of Lyme disease in which the spirochete invades peripheral and central nervous system (CNS). Symptoms of LNB include; Bannwarth’s Syndrome, Lymphocytic Meningitis, and Cranial Neuritis. OspA leads to the complex inflammation process in the brain. When borrelia enter the CNS they encounter immune cells of the body such as monocytes, macrophages, and dendritic cells. These cells then release proinflammatory cytokines as well as chemokines. An increase in these cytokines and chemokines has been seen in the CSF of patients suffering from LNB. 1. The first step of the inflammatory response is when OspA is recognized by a monocytic cell. 2. In step two the monocytic cell releases the chemokine CXCL13. 3. In the third step of the inflammatory process, B-lymphocytes move into the CSF. 4. During the 4th step, the B-lymphocytes are turned into plasma cells. 5. In the 5th step antibodies are created, causing he the 6. final step where borrelia are killed. This response can be helpful in killing borrelia but also can cause harmful inflammation. 2



OspA Vaccination

Lyme disease can be prevented by avoiding areas with ticks, wearing proper attire, and using DEET (N,N-diethy-m-toluamide). However prevention by using an Osp of Borrelia as a vaccine could also be an effective measure. 3 Borrelia shows abundant OspA and OspB, both of the proteins are very similar to each other; their amino acid sequences are 50% the same 1 . However OspA is more studied than OspB, and many studies related to OspA structure are developing and creating to make efficient vaccine against other Lyme diseases 4. The first vaccine against B. burgorferi sensu stricto was created targeting the OspA strain successfully 2 However this vaccine is unique in that it only works while Borrelia are still in the gut expressing OspA. (Ding) LYMErix, was discontinued in 2002 due to various weaknesses of the vaccine including its <80% efficacy, requirement for 3 doses, lack of data concerning the effects of the vaccine on children, and limitation of protection to the North American species of Borrelia. 6 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 <<SHOW FAB HIGHLIGHTED ON 1FJ1>> is a murine monoclonal antibody that binds strongly <<SHOW INTERACTION HIGHLIGHTED (ZOOMED IN) ON 1FJ1>> to OspA <<SHOW OSPA HIGHLIGHTED ON 1FJ1>>, and how effective a vaccine is correlated with LA-2 binding. 5



Structure of OspA

OspA is made of 21 anti-parallel β-strands and a single α-helix. 5 OspA is unique due to its dumbbell shape that contains two globular domains connected by a single layer β-sheet. 7 There are three loops <<ALL 3 LOOPS> located at the C-terminus that are important in binding, and amino acids that are unconserved between different strains <<ALL 3 RESIDUES>>. Loop 1, residues 206 and 216, has an important role in binding due to a large exposed surface area, high mobility. Loop 2, residues 224-233, and Loop 3, residues 246-257, are also areas that are involved in binding. LA-2 recognizes OspA Bb, but does not recognize OspA from Bg.and Ba. Between Bb. and Ba. genetic sequences are generally invariant, but two residues change between the species, ALA 208 in Bb. is GLN in Ba., and 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 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



References

1Connolly, SE and Benach JL. 2005. The Versatile Roles of Antibodies in Borrelia Infections. Microbiology 3: 411-420. 2Rupprecht T, Koedel U, Fingerle V and Pfister H-W. 2008. The Pathogenesis of Lyme Neuroborreliosis: From Infection to Inflammation. Molecular Medicine 14(3-4): 205-212. 3Nigrovic L, Thompson K. 2007. Epidemiology and Infection. The Lyme Vaccine: A Cautionary Tale. 135(1)1-8. 4Battisti JM, Bono JL, Rosa PA, et al. 2008. Outer Surface Protein A Protects Lyme Disease Spirochetes from Acquired Host Immunity in the Tick Vector. Infect. Immun. 76(11): 5228-5237. 5Ding W, Huang X, Yang X, Dunn J, et al. 2000. Structural Identification of a Key Protective B-Cell Epitope in Lyme Disease Antigen Osp A, Journal of Molecular Biology 302(5): 1153-1164. 6Plotkin S. 2011. Clinical Infectious Diseases. Correcting a Public Health Fiasco: The Need for a New Vaccine Against Lyme Disease. 52(3):s721-275. 7Koide? Who used this? 8Livey I, O’Rourke M, Traweger A, Savidis-Dacho H, Crowe B, Barrett P, Yang X, Dunn J, Luft B. 2011. Clinical Infectious Diseases. A new approach to a Lyme Disease Vaccine. 52(3):s266-s270.


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