User:Marvin O'Neal/OspA
From Proteopedia
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Introduction
Lyme disease is caused by tick-borne Borrelia from ticks in the family Ixodidae. 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
OspA & Lyme Disease
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.
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 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)
Structure of OspA
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).
