User:Marvin O'Neal/OspA

2012-05-02T09:39:51Z

Jenny Kim Kim:

<Structure load="1fj1" size="350" frame="true" align="right" name="OspA-secondary" caption="Outer surface protein A (OspA) ([[1fj1|1FJ1]], chain F) showing secondary structures." scene="Studio:G2SecL03/Ospa_default/5"/>

Outer Surface Protein A (OspA) is a major lipoprotein found on the surface of [http://en.wikipedia.org/wiki/Spirochaete spirochetes] from the genus [http://en.wikipedia.org/wiki/Borrelia Borrelia] and is comprised of 21 anti-parallel β-strands and a single α-helix. OspA's expression is regulated at different points in time, from being downregulated during the tick's feeding process on its host to being upregulated in the host's cerebrospinal fluid (CSF) to induce inflammatory response, resulting in acute Lyme [http://en.wikipedia.org/wiki/Neuroborreliosis neuroborreliosis]. OspA has also been used as a vector in working towards the development of a vaccine for [http://en.wikipedia.org/wiki/Lyme_disease Lyme disease].


NOTE: Red text indicates changes/additions I've made and this style is pertinent thoughts/questions we should consider/address. All of this will be cleaned up for the final submitted page. ~Kim

<h2>Introduction</h2>

Lyme disease is caused by the spirochete Borrelia and spread via hard-bodied ticks belonging to the family [http://en.wikipedia.org/wiki/Ixodidae Ixodidae]. The Borrelia spirochetes are motile, helical organisms have several lipoproteins exposed on the surfaces of their membranes that invoke a response from host immune systems. The predominant group of these is classified as the outer surface proteins (Osps). Both the pathogenesis of Lyme disease as well as the host's immune response stem from the effects of the spirochete's presence and involvement in the system.<ref name="connolly">PMID: 15864264</ref>

The major strain of Borrelia in the United States is [http://en.wikipedia.org/wiki/Borrelia_burgdorferi Borrelia burgdorferi] sensu stricto (Bb.), with 20-100 cases of Lyme disease being reported per 100,000 people. In Europe, Lyme disease cases are more prevalent, with 100-130 diagnoses per 100,000 people, but are caused by the spirochetes [http://en.wikipedia.org/wiki/Borrelia_afzelii Borrelia afzelii (Ba.)] and [http://en.wikipedia.org/wiki/Borrelia_garinii Borrelia garinii (Bg.)] in addition to B. burgdorferi.<ref name="rupprecht">PMID: 18097481</ref><ref name="ding">PMID: 11183781</ref>

Do we want to mention the number of Borrelia strains but the fact that there are only 4 which are infectious to humans? - need a reference though


Lyme disease is a debilitating condition that begins with a characteristic bullseye rash known as an [http://en.wikipedia.org/wiki/Erythema_chronicum_migrans erythema migrans (EM)] as well as the development of lesions on other parts of the body, not just at the site of the tick's attachment to its host. Secondary stage symptoms include affecting the heart, joints, and both the central and peripheral nervous systems. Borrelia have two major outer surface lipoproteins that are involved in Lyme disease: OspA and OspB. OspA is used in adhering to the tick's gut by binding with the tick receptor (TROSPA)

Think a blurb about this would be useful- there isn't a wiki page for easy reference.

During feeding, OspA is downregulated in order to evade an immune response from the incoming host blood into the gut, releasing the Borrelia from the gut wall and migrating into the tick's salivary glands, thereby allowing it to enter the host through the bite. This is evidenced by the fact that patients with Lyme disease have been found to not possess OspA antibodies in the early stages of the disease.<ref name="connolly">PMID: 15864264</ref><ref name="rupprecht">PMID: 18097481</ref> OspA is the protein most related to acute Lyme neuroborreliosis (LNB), the neurological manifestations of Lyme disease.

We mention "two" proteins involved in Lyme Disease and just 'name' OspB but we don't even have a sentence or two about it in this part?


Once inside the host, the Borrelia has a great number of mechanisms available to actively suppress the host's immune system response and neutralize its effector mechanisms, such as the expression of another outer surface protein, OspC, which prevents susceptibility to the host's [http://en.wikipedia.org/wiki/Innate_immune_system innate immunity] and [http://en.wikipedia.org/wiki/Complement_system complement systems]. Additionally, Borrelia is capable of suppressing many of its surface proteins to reduce its detectability, but can also utilize protective means by temporarily expressing them when needed.


<h2>OspA & Lyme Disease</h2>

Acute Lyme Neuroborreliosis (LNB) is part of the second stage of Lyme disease in which the spirochete invades the peripheral and central nervous systems (CNS). Symptoms of LNB include: Bannwarth’s Syndrome, Lymphocytic Meningitis, and [http://www.rightdiagnosis.com/sym/cranial_neuritis.htm Cranial] and [http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001619/ Peripheral Neuritis]. The presence of OspA in the cerebrospinal fluid (CSF) is responsible for this complex inflammatory response in the brain that leads to the neuroborreliosis.


[[Image:G2L03-OspA-mechanism.jpg|thumb|300px|Mechanism of the host inflammatory response to OspA]]

There are six steps involved in the host's inflammatory response to OspA: <ref name="rupprecht">PMID: 18097481</ref> 
<ol>
<li>When the Borrelia enter the host’s CNS they encounter several different types of immune cells such as [http://en.wikipedia.org/wiki/Monocyte monocytes], [http://en.wikipedia.org/wiki/Macrophages macrophages], and [http://en.wikipedia.org/wiki/Dendritic_cells dendritic cells]. While in the CSF, outer surface protein A (OspA) is upregulated and it’s increased expression promotes recognition by a specific receptor on a monocyte.</li>

<li>The OspA-bound monocyte then releases proinflammatory [http://en.wikipedia.org/wiki/Cytokine cytokines] (i.e. [http://en.wikipedia.org/wiki/Interferon interferon]), as well as [http://en.wikipedia.org/wiki/Chemokine chemokines], such as [http://en.wikipedia.org/wiki/CXCL13 CXCL13]. In patients with LNB, there is an observed increase in the levels of these cytokines and chemokines in their CSF. The production of chemokines leads to the recruitment of other immune cells to the site of infection.</li>

<li>[http://en.wikipedia.org/wiki/B_lymphocyte B-lymphocytes] respond to the new concentration gradient of CXCL13 between the blood and CSF and migrate into the CSF.</li>

<li>B-lymphocytes undergo [http://en.wikipedia.org/wiki/Receptor-mediated_endocytosis receptor-mediated endocytosis], consuming the OspA antigens present in the CSF, thereby triggering its activation. The B-lymphocytes then are able to differentiate and mature into [http://en.wikipedia.org/wiki/Plasma_cells plasma cells].</li>

<li>The plasma cells create large quantities of anti-OspA antibodies specific to this strain of Borrelia and release them into the CSF.</li>

<li>The anti-OspA antibodies will then bind to the OspA on the spirochete’s membrane, thus killing the Borrelia.</li>
</ol>


This process is two-sided in the sense that the OspA aids in the pathogenesis of new symptoms (neuroborreliosis) through the chemokine’s actions, as well as initiating the signaling cascade to destroy itself.


<h2>OspA Vaccination</h2>

Risk of developing Lyme disease can be mitigated by staying clear of areas with populations of ticks, wearing proper attire to minimize easily bitten areas of the body, and using insect repellents containing [http://en.wikipedia.org/wiki/DEET DEET] (N,N-diethy-m-toluamide). However, another effective means for prevention could be possible by using an outer surface protein from Borrelia in the development of a vaccine <del>could also be an effective measure</del>.<ref name="nigrovic">PMID: 16893489</ref>


The membrane composition of Borrelia is abundant in both OspA and OspB, and the two proteins share a 53% similarity in their primary sequences. Both are also 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 much more variability.<ref name="becker">PMID: 15713683</ref>



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


<h2>Structure of OspA</h2>

<Structure load="1fj1" size="350" frame="true" align="right" name="OspA-manip" caption="Outer surface protein A (OspA) ([[1fj1|1FJ1]], chain F)" scene="Studio:G2SecL03/Ospa_3loopscartoon/3"/>


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 <scene name='Studio:G2SecL03/Ospa-3loops/4' target="OspA-manip">three key loops</scene> located at the C-terminus that are important in binding, and <scene name='Studio:G2SecL03/Ospa-3residues-nor/3' target="OspA-manip"> three residues that are unconserved between different strains</scene> <scene name='Studio:G2SecL03/Ospa-3residues-r/2' target="OspA-manip">(toggle residue R-groups)</scene> <scene name='Studio:G2SecL03/Ospa-3loops3res/1'>Three loops and three residues (with R-groups showing)</scene>.
 
Loop 1 <<LOOP 1>>, residues 206 and 216, has an important role in binding due to a large exposed surface area, high mobility. Loop 2 <<LOOP 2>>, residues 224-233, and Loop 3 <<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 <<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


<h3>Reference List of Available Scenes for OspA</h3>
<ul>
<li><scene name='Studio:G2SecL03/Ospa_3loopscartoon/3' target="OspA-manip">Reset model</scene> </li>
<li><scene name='Studio:G2SecL03/Ospa-3loops/4' target="OspA-manip">Three key loops</scene> (close up)</li>
<li><scene name='Studio:G2SecL03/Ospa-3residues-nor/3' target="OspA-manip">Three key residues</scene> (Ala208, Ala215 and Asn251 in B. burgdorferi, also hides R-groups)
<ul>
<li><scene name='Studio:G2SecL03/Ospa-3residues-r/2' target="OspA-manip">Display R-groups</scene> of Ala208, Ala215 and Asn251</li>
</ul>
</li>
<li><scene name='Studio:G2SecL03/Ospa-3loops3res/1' target="OspA-manip">Three loops and all three residues (with R-groups showing)</scene></li>
</ul>

<h2>In-Prog References</h2>
Not fully structured yet with -ref- tags, just organizing all reference information for ease 

<ul>
<li>1 Connolly, SE and Benach JL. 2005. The Versatile Roles of Antibodies in Borrelia Infections. Microbiology 3: 411-420. 
http://www.nature.com/nrmicro/journal/v3/n5/abs/nrmicro1149.html 
PMID: 15864264

<li>2 Rupprecht 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. 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2148032/ 
PMID: 18097481

<li>3 (now 4) Nigrovic L, Thompson K. 2007. Epidemiology and Infection. The Lyme Vaccine: A Cautionary Tale. 135(1)1-8. 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2870557/ 
PMID: 16893489

<li>4 Battisti 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. 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2573341/ 
PMID: 18779341

<li>5 (now 3) Ding 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. 
http://www.sciencedirect.com/science/article/pii/S0022283600941196 
PMID: 11183781

<li>6 Plotkin S. 2011. Clinical Infectious Diseases. Correcting a Public Health Fiasco: The Need for a New Vaccine Against Lyme Disease. 52(3):s721-275. 

<li>7 Koide? Who used this? 

<li>8 Livey 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. 

<li>9 (now 5) Becker M et al. 2005. Structural Investigation of Borrelia burgdorferi OspB, a BactericidalFab Target. JOURNAL OF BIOLOGICAL CHEMISTRY. 280(17):17363–17370. 
http://www.jbc.org/content/280/17/17363.long 
PMID: 15713683
 
</ul>

<h2>References</h2>
<references />

<h2>External Links</h2>
<ul>
<li>[http://www.who.int/ith/diseases/lyme/en/index.html World Health Organization: Lyme Disease]
<li>[http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002296/ PubMed Health: Lyme Disease]
<li>[http://www.aldf.com/ American Lyme Disease Foundation]
</ul>

<h2>Proteopedia Page Contributors and Editors</h2>
[http://proteopedia.org/wiki/index.php/User:Kimberly_Slade Kimberly Slade], [http://proteopedia.org/wiki/index.php/User:Cara_Lin Cara Lin], [http://proteopedia.org/wiki/index.php/User:Andrea_Mullen Andrea Mullen], [http://proteopedia.org/wiki/index.php/User:Jenny_Kim_Kim Jenny Kim Kim]