User:Marvin O'Neal/OspA

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Revision as of 05:48, 30 April 2012

OspA (Outer Surface Protein A) is Need more info here

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

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 Do we want to include more info here?. The predominant strain of Borrelia in the United States is 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 instead are caused by the spirochetes Borrelia afzelii (Ba.) and Borrelia garinii (Bg.).^[1] The Ba. and & Bg. wiki pages are 'slightly sparse'; I don't know if we want to include those links or not... Also, do we want to mention the number of Borrelia strains but the fact that there are only 4 which are infectious to humans?

Lyme disease is a debilitating condition that begins with a characteristic bullseye rash known as an erythema migrans (EM) as well as lesions developing throughout all over the body. 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 immune response from the incoming host blood into the tick's gut, releasing the Borrelia from the gut wall and migrating into the tick's salivary glands, thereby allowing it to enter the host. OspA is the protein most related to acute Lyme neuroborreliosis (LNB), the neurological manifestations of Lyme disease. 2 We mention "two" proteins involved in Lyme Disease and just 'name' OspB but we don't even have a sentence or two about it?

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

In-Prog References

Not structured yet with -ref- tags, just organizing all reference information


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
doi:10.1038/nrmicro1149
http://www.ncbi.nlm.nih.gov/pubmed/15864264
PMID: 15864264

2 (now 1) 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/
http://www.ncbi.nlm.nih.gov/pubmed/18097481
PMID: 18097481

3 Nigrovic L, Thompson K. 2007. Epidemiology and Infection. The Lyme Vaccine: A Cautionary Tale. 135(1)1-8.


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.


5 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
http://dx.doi.org/10.1006/jmbi.2000.4119
http://www.ncbi.nlm.nih.gov/pubmed/11183781
PMID: 11183781

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.


7 Koide? Who used this?


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.

References

1. ↑ 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