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Borrelia Antigen and Different Types Part II

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Relapsing fever is transmitted via arthropod vectors. The human body louse (Pediculus humanus corporis) transmits Borrelia recurrentis, the causative organism of louse-borne relapsing fever (LBRF), while Ornithodoros ticks are vectors for the at least 15 different species of Borrelia that cause endemic or tick-borne relapsing fever (TBRF).    

While humans are the only known host for the LBRF spirochete, the TBRF-causing Borrelia species (with the exception of B. duttonii) have their reservoirs in small rodents and have been found in several locations worldwide. In North America, three species of Borrelia cause TBRF, and several outbreaks of the disease have been described. In East Africa, B. duttonii is the principal cause of TBRF.

Antibody responses against relapsing fever Borrelia species are primarily directed against outer surface lipoproteins. Two major protein groups have been identified, namely, variable small proteins (approximately 22 kDa) and variable large proteins (approximately 38 kDa). These proteins have been studied most thoroughly for B. hermsii and B. turicatae. It is probable that all of the relapsing fever Borrelia species share the same antigenic variation scheme as that described in detail for these two species.

When spirochetes are present in blood, they must evade the immune defense systems. Before the acquired immune responses lead to the production of antibodies, the alternative pathway of complement operates as a major innate immune defense system against the invading organisms. In the presence of antibodies, complement acts as an effector system, mainly via the classical pathway (CP). Both pathways lead to coating of the target surface with C3b. Together with their cleavage products, such as iC3b, the C3b molecules opsonize the target for phagocytosis. Further activation can lead to the formation of lytic membrane attack complexes. To avoid overconsumption of the components of the complement cascade and to protect self-cells from harmful attacks, complement activation must be tightly regulated. This is mediated by regulatory proteins in plasma and on cell surfaces.

The major fluid-phase regulators of complement are factor H (FH), for antibody-independent alternative pathway activation, and C4b-binding protein (C4BP), for antibody-dependent CP activation. These regulators accelerate decay of the C3 convertases (C3bBb and C4b2a, respectively) and act as cofactors for the irreversible inactivation of C3b and C4b, respectively. As a net effect, these functions prevent complement-mediated destruction of the target in both the absence and presence of antibodies. Acquisition of the host plasma complement regulator FH has been shown to be beneficial for complement evasion among other spirochetes, such as Borrelia burgdorferi sensu stricto and B. afzelii, which express at least two FH binding proteins. Also, the relapsing fever agents B. hermsii and B. parkeriihave been shown to bind FH, while no binding has been observed for B. turicataeB. hermsiiexpresses a unique 20kDa outer surface protein (FhbA) responsible for FH binding.

The bacteria that cause human Lyme disease belong to a group of at least 15 species, referred to as Borrelia burgdorferi sensu lato, or the Lyme disease agent bacterial group. Among these, B.burgdorferi sensu stricto causes Lyme disease in North America, while in Europe and eastern Asia Borrelia afzelii, Borrelia garinii, and Borrelia bavariensis sp. nov. are the best-known causes. However, more recently, Borrelia bissettii, Borrelia lusitaniae, Borrelia spielmanii, and Borrelia valaisiana have been isolated from Lyme disease patients. Other species in this bacterial group, such as Borrelia japonica and Borrelia sincia in Asia, have not been associated with human disease. To date, genome sequences have been reported for 14 B. burgdorferi isolates, two B. afzelii isolates, two B. garinii isolates, one B. bavariensis sp. nov. isolate and 1 isolate of unassigned species.

The complete genome sequences for three additional Borrelia species: B. valaisiana isolate VS116, B. bissettii isolate DN127 clone 9, and B. spielmanii isolate A14S. DNA samples from low-passage isolates were sequenced to minimize plasmid loss, and genomes are sequenced to about 8-fold coverage as previously described. Genome annotation is performed using the JCVI Prokaryotic Annotation Pipeline . The DN127 chromosome and 35 of 39 plasmid sequence contigs are closed, but in order to maximize the use of available funds, the sequences of a few replicons are not closed and some gaps remained in these sequences (two chromosomes and one cp9 and three cp32 plasmids, because they are much less variable than the other plasmids).

 

These three genome sequences include 3,914,891 bp in total (1,258,865, 1,403,466, and 1,252,560 bp for strains VS116, DN127, and A14S, respectively), with an average of 1,304,497 bp/genome. Like the sequences of other Borrelia species, they include numerous linear plasmids (6, 7, and 7, respectively) and circular plasmids (2, 2, and 2, respectively). Plasmid numbers in these three strains range from 11 in VS116 and 12 in A14S to 16 in DN127. Plasmids that are very similar to B. burgdorferi sensu stricto cp26, cp32 (7 in DN127, versus 3 in the other two strains analyzed), and lp54 plasmids are present in each of these isolates, and DN127 also contains an unusual fusion of four partial cp32 plasmids. Plasmids with predicted lp17 compatibility are also present in all three genomes, making it the only other plasmid type, in addition to cp26 and lp54, to be found in all 23 B. burgdorferi sensu lato sequenced genomes. However, the gene contents of the lp17s are much more variable than the other universally present plasmids.

The detailed analyses of these genome sequences will be a major step forward in attaining a complete understanding of B. burgdorferi sensu lato diversity. They will contribute to the development of species- and group-specific vaccines and diagnostic tools, as well as inform us whether these species are in genetic contact with the more-common Lyme disease-associated agents.

Reference

[1] Barbour A G, Hayes S F. Biology of Borrelia species. [J]. Microbiological Reviews, 1986, 50(4):381-400.

[2] Van H C, Comberbach M, De G D, et al. Evaluation of the safety, reactogenicity and immunogenicity of three recombinant outer surface protein (OspA) lyme vaccines in healthy adults [J]. Vaccine, 1996, 14(17–18):1620-1626.

[3] Kraiczy P. Whole-genome sequences of Borrelia bissettii, Borrelia valaisiana, and Borrelia spielmanii. [J]. Journal of Bacteriology, 2012, 194(2):545-6.

[4] Cutler S J, Moss J, Fukunaga M, et al. Borrelia recurrentis characterization and comparison with relapsing-fever, Lyme-associated, and other Borrelia spp.[J]. International Journal of Systematic Bacteriology, 1997, 47(4):958-68.


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