User:Marvin O'Neal/OspC
From Proteopedia
Imporance of OspC in Lyme disease
Lyme disease is caused by Borrelia burgdoferi, a spirochete that is identified in black-legged tick, Ixodes scapulars. It is the most prevalent tick-borne disease in North America and Europe. Humans infected with Lyme disease begin with unusal skin lesions (erythema migrans), which later develop into more severe neurological and cardiac symptoms if it is not treated. [1] Thus, B. burgdoferi persists in human by interacting its surface-exposed proteins with the molecules of the host. This interaction of its outer surface proteins (Osps) is very crucial for the pathogenic pathway of Lyme disease. When the ticks bite on human, B. burgodoferi in the unfed ticks, which colonize in the midgut, produces OspA, OspB but no OspC. However, the tick migrates from guts to salivary gland during feeding period, OspC is upregulated, thereby inducing OspC synthesis and inhibiting the expression of OspA and OspB due to changes in environmental temperature and pH.[2] Therefore, the vaccine against Lyme disease named OspA-based LYMErix vaccine was available for human use from 1998 to 2002. However, it was withdrawn because of its vaccine-associated autoimmune risk factors. In addition, the majority of ticks reside in the tick silva do not have OspA, but OspC is present during the early infection. Nowadays, scientists are trying to find new OspC-based vaccine as an effective target of immunity. Even though OspC has stable antigenic site on its outer surface during infection, the vaccine of recombinant anti-OspC are effective only for the spirochetes with identical sequence of OspC because OspC is a highly variable protein.[3] Its genetic diversity at OspC locus can be categroized into 19 outer surface major groups (oMGs), denoted by type A to S. Based on its alignment sequence, the sequence variation within a major group is 1% whereas approximately 15% between major groups. However, only four invasive allelic groups: A, B, I (1f1m), and K, are responsible for causing human Lyme disease.[4] Therefore, polymorphism of OspC driven by the ecological interaction in natural B. burgdoferi plays an essential role in discovering anti-OspC based vaccine to prevent the prevalence and risk of human Lyme disease.
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Lyme disease and Ecology
![Life cycle of tick.[[1]]](/wiki/index.php/Image:Life_cycle_of_tick.png)
The number of reported cases of Lyme disease is increasing annually in highly focused geographic locations of the United States. Thus, the abundance of infected ticks with B. burgdorferi in natural ecosystems is critical for the risk of human Lyme disease. In tick life cycle, the larval ticks are uninfected with B. burgdorferi. However, B. burgdorferi infection begins while feeding on the blood of natural reservoir hosts such as mice, squirrels, shrews and other small vertebrates. Undergoing successive life stages, the infected nymphal ticks can transmit B. burgdorferi to incidental vertebrates, including humans. The ecological interaction between the competence of reservoir hosts and the ticks is the underlying measure of human Lyme disease risk.[5]
Ecological factors responsible for human Lyme disease risk
- Vertebrate Community Composition[6]: Two types of environment that the vertebrate hosts reside, which is also called vertebrate host density are interspecific community, which involves organisms of different species and intraspecific community, which is composed of organisms of same species. The hosts living in the community within different species or same species strongly affects the proportion of infected nymphal tick that can cause human Lyme disease.
- Distribution frequency of particular oMGs[7]: After taking blood meal from their hosts, the proportion of host-seeking nymphs infected with each oMG differs among oMGs. As only four types of oMGs (A, B, I and K) are responsible for systemic human Lyme disease, the host-seeking nymphs that have high distribution frequency of four invasive oMGs is one of the standard measures of human Lyme disease risk.
- Transmission Probability[7]: The transmission probability of each oMGs from individual species differs. The higher the transmission probability of a particular oMG from vertebrate host, the higher the chance of carrying that particular oMG by the ticks after receiving blood meal from their hosts is. Thus, it is one of the parameters that contributes the prevalence of human Lyme disease.
Dilution Effect Model [8]
![Map illustrating prevalence of Lyme disease in the Untied States by CDC.[[2]]](/wiki/index.php/Image:Lyme_Disease_Risk_Map.gif)
This conceptual model characterizing the ecological interaction between vertebrate host community and distribution frequency of invasive oMGs determines the cases of human Lyme disease. The principal natural reservoir host for the epidemic of Lyme disease in northeastern and central United States is the presence of only white-footed mice (Peromyscus leucopus) population, which has both high frequency distribution in all four human infectious oMGs and high transmission probabilities of oMGs A, B, I and K.[7] In addition, ticks are least likely to parasitize inefficient reservoir hosts, thereby increasing high infection prevalence in the tick population, which enhances the risk of exposure of Lyme disease in humans. Therefore, dilution-effect model propses that maintaining high diversity of vertebrate host community may dilute the power of white-footed mouse by increasing the degree of specialization of ticks on inefficient hosts. This model strongly demonstrates the relationship between species diversity in the community of hosts and the risk of human exposure to Lyme disease. These ecological driving forces described in the model are useful tools in predicting the prevalence and risk of human Lyme disease.
Primary and Secondary structure of OspC
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| 1ggq, resolution 2.51Å () | |||||||||
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| Ligands: | |||||||||
| Related: | 1f1m, 1osp, 1fj1 | ||||||||
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| Resources: | FirstGlance, OCA, RCSB, PDBsum | ||||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||||
The model presented is B31 strain (residues 38-201), which is also known as oMG A. This is one of four invasive oMGs that are responsible for systematic Lyme disease. In crystal structure, OspC exists as a dimer with the coordination of divalent ion, which is modeled as a magnesium ion. Each subunit is predominantly helical, consisting of five parallel
, two short antiparallel
and six
. The N and C termini at the membrane proximal end of two long alpha helices,
(residues 38-76) and
(residues 170-201) are in close proximity to each other. At the membrane distal end, there are three remaining alpha helices,
(residues 95-112),
(residues 121-145), including a short
(residues 152-159). At the end of membrane surface, the connection between helices α1 and α2 forms two short anti-parallel β-strands,
(residues 79-80),and
(residues 88-89) are formed. Based on the alignment of all oMGs, towards the membrane proximal end, the surface-exposed residues on α1 and α5 are highly conserved, resulting positively charged surface. Other than those on helices, α1 and α5, the surface-exposed residues on the remaining regions of OspC molecule are variable.
Evolutionary Conservation of OspC
Since OspC locus is the most variable gene, the sequence alignment of all oMGs reveals that towards the membrane proximal end, the surface-exposed residues on α1 and α5 are highly , resulting positively charged surface. Other than those on helices, α1 and α5, the surface-exposed residues on the remaining regions of OspC molecule are variable.[9]
OspC Model
At the membrane distal region, the six loop regions, including two β-strands illustrates the of OspC due to the presence of variable surface-exposed residues among OspC isolates. [10] However, among these variable regions, the outer surface-exposed residues connecting the helices α1 and α2, forming the loops, (residues 74-78), (residues 81-87), (residues 90-93)and two short beta strands, β1 and β2, and also (residues 146-150) are more highly variable than those present in the loops, (residues 115-119)and (residues 161-169). Consequently, the surface potential of red region that projects away from the membrane is negatively charged and mainly involved in the protein-protein or protein-ligand interactions.[9] Only four types of oMGs (A, B, I and K), whose surface potential in red region is highly negative relative to non-invasive one plays a major role in pathogenesis of human Lyme disease. [4] The residue, , located on the red region at the membrane distal end is unique that the replacement of other residues except His82, Lys82, Gln82, which are present only in four invasive oMGs enhances the possibility of turning invasive strains to non-invasive one. Thus, the stronger the electrostatic potential on red region, the higher the chance for OspC to bind with positively charged host ligands. Therefore, the alternation of an amino acid residue at the 82nd position on red region not only demonstrates OspC polymorphism, but also points out the probability for turning invasive strains to non-invasive strains.[4]
OspC-based vaccine against Lyme disease
The OspC-based vaccine is currently a target to elicit protection against Lyme disease. Because of the polymorphism of OspC, the recombinant OspC vaccine, targeting the antigenic site of specific OspC type is ineffective for B. burgdorferi with different OspC types. Therefore, the development of vaccine that recognizes the antigenic determinant on the variable regions of multiple OspC types is required in order to effectively activate human immune response. Based on the mapping of epitope-containing regions from oMGs: A, B, K and D, the experiment-based tetravalent chimeric vaccine is developed to tigger anti-ABKD response. [11] Then, taking advantage of tetravalent ABKD construct, octavalent chimeric vaccine also known as OspC-A8.1, recognizing additional epitopes of oMGs: C, E, N and K, is experimented in mice by using western blotting and ELISA. [3] The constructs of tetravalent and octavalent chimeric vaccine are the underlying development of producing multiple OspC types vaccine to prevent the prevalence and risk of human Lyme disease.
References
- ↑ Burgdorfer W, Barbour AG, Hayes SF, Benach JL, Grunwaldt E, Davis JP. Lyme disease-a tick-borne spirochetosis? Science. 1982 Jun 18;216(4552):1317-9. PMID:7043737
- ↑ Templeton TJ. Borrelia outer membrane surface proteins and transmission through the tick. J Exp Med. 2004 Mar 1;199(5):603-6. Epub 2004 Feb 23. PMID:14981110 doi:10.1084/jem.20040033
- ↑ 3.0 3.1 Earnhart CG, Marconi RT. An octavalent lyme disease vaccine induces antibodies that recognize all incorporated OspC type-specific sequences. Hum Vaccin. 2007 Nov-Dec;3(6):281-9. Epub 2007 Jul 2. PMID:17921702
- ↑ 4.0 4.1 4.2 Kumaran D, Eswaramoorthy S, Luft B, Koide S, Dunn J, Lawson C, and Swaminathan S. 2001. Crystal Structure of Outer Surface Protein C (OspC) from the Lyme Disease Spirochete, Borrelia burgdorferi. The EMBO Journal 20(5): 971-978. DOI: 10.1093/emboj/20.5.971
- ↑ LoGiudice K, Ostfeld RS, Schmidt KA, Keesing F. The ecology of infectious disease: effects of host diversity and community composition on Lyme disease risk. Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):567-71. Epub 2003 Jan 13. PMID:12525705 doi:10.1073/pnas.0233733100
- ↑ Brisson D, Dykhuizen DE. ospC diversity in Borrelia burgdorferi: different hosts are different niches. Genetics. 2004 Oct;168(2):713-22. PMID:15514047 doi:10.1534/genetics.104.028738
- ↑ 7.0 7.1 7.2 Brisson D, Dykhuizen DE. A modest model explains the distribution and abundance of Borrelia burgdorferi strains. Am J Trop Med Hyg. 2006 Apr;74(4):615-22. PMID:16606995
- ↑ Ostfeld R and Keesing F. 2001. Biodiversity and Disease Risk: the Case of Lyme Disease. Conservation Biology 14.3 (2000): 722-728.DOI: 10.1046/j.1523-1739.2000.99014.x.
- ↑ 9.0 9.1 Eicken C, Sharma V, Klabunde T, Owens RT, Pikas DS, Hook M, Sacchettini JC. Crystal structure of Lyme disease antigen outer surface protein C from Borrelia burgdorferi. J Biol Chem. 2001 Mar 30;276(13):10010-5. Epub 2001 Jan 3. PMID:11139584 doi:10.1074/jbc.M010062200
- ↑ Earnhart C, LeBlanc D, Alix K, Desrosiers D, Radolf J, and Marconi R. 2010. Identification of residues within ligand-binding domain 1 (LBD1) of the Borrelia burgdorferi OspC protein required for function in the mammalian environment. Molecular Microbiology 76(2): 393-408. DOI: 10.1111/j.1365-2958.2010.07103.x
- ↑ Christopher G. Earnhart, Eric L. Buckles, Richard T. Marconi. "Development of an OspC-based tetravalent, recombinant, chimeric vaccinogen that elicits bactericidal antibody against diverse Lyme disease spirochete strains, Vaccine." 25(3) 466-480 (2007). DOI: 10.1016/j.vaccine.2006.07.052
