Gene/Protein Disease Symptom Drug Enzyme Compound
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Both soluble and cell-mediated components are involved in the innate immune response of arthropods. Injection of Borrelia burgdorferi, the Lyme disease agent, results in the secretion of defensin into the hemolymph of the ixodid tick, Dermacentor variabilis. The presence of the peptide is observed as early as 15 min post-challenge and remains present through 18 h post-challenge. As observed in insects and soft ticks, the transcript for defensin is detected as early as 1 h post-challenge in D. variabilis. RT-PCR resulted in an amplicon of 624 bp with a 225 bp region that translates to a 74 amino acid preprodefensin. The defensin encoding region was amplified, cloned and sequenced from the hemocytes. It appears as though defensin is stored in the granulocytes of the hemolymph and secreted into the hemolymph upon bacterial insult. The role of defensin as a contributing factor in determining vector competency is discussed.
Insect Biochem Mol Biol 2003 Nov
PMID:An arthropod defensin expressed by the hemocytes of the American dog tick, Dermacentor variabilis (Acari: Ixodidae). 1456 61

We investigated mechanical unfolding of Borrelia burgdorferi outer surface protein A (OspA), a Lyme disease antigen containing a unique single-layer beta-sheet, with atomic force microscopy (AFM). We mechanically stretched a monomeric unit, rather than a tandem repeat, by pulling it from its N and C-terminal residues without using intervening polymer as a spacer. We detected two peaks in the force-extension profile before the final rupture of a fully extended polypeptide, which we interpreted as unfolding of multiple substructures in OspA. The double-peaked unfolding curves are consistent with results of previous thermodynamic studies showing two cooperative units in OspA. The mechanical unfolding processes were reversible, and the two substructures refolded within one second. Mutations near the boundary of the two thermodynamic cooperative units reduced the height of the first unfolding peak to undetectable levels and marginally affected the second one, indicating that the boundary between the two mechanical substructures is related to that previously assigned between the thermodynamic cooperative units. Based on a "worm-like chain" analysis of our AFM data, we propose a model for mechanical unfolding of OspA, where nearly a half of the chain is stretched with minimal resistive force, followed by sequential breakdown of C-terminal and N-terminal substructures. Based on these results, we discuss similarities and differences between mechanical and thermodynamic unfolding reactions of OspA. This work demonstrates that AFM study of monomeric proteins can elucidate details of the intramolecular mechanics of protein substructures.
J Mol Biol 2003 Nov 07
PMID:Unfolding mechanics of multiple OspA substructures investigated with single molecule force spectroscopy. 1458 95

All isolates of the spirochete Borrelia burgdorferi contain multiple, different plasmids of the cp32 family, each of which contains a locus encoding Erp surface proteins. Many of these proteins are known to bind host complement regulatory factor H, enabling the bacteria to avoid killing by the alternative complement pathway during vertebrate infection. In the present study, we characterized the erp loci and cp32 plasmids of strains N40, Sh-2-82, and 297 and compared them to the previously determined cp32 sequences of type strain B31. Bacteria of strain N40 contain 6 different cp32s, those of Sh-2-82 contain 10, and 297 bacteria contain 9 cp32s. Significant conservation between all strains was noted for the cp32 loci responsible for plasmid maintenance, indicating close relationships that appear to correspond with incompatibility groups. In contrast, considerable diversity was found between erp gene sequences, both within individual bacteria and between different strains. However, examples of identities among erp loci were found, with strains Sh-2-82, 297, and B31 each containing three identical loci that likely arose through intrabacterial genetic rearrangements. These studies also found the first evidence of large-scale genetic exchanges between Lyme disease spirochetes in nature, including the apparent transfer of an entire cp32 plasmid between two different bacteria.
J Mol Evol 2003 Sep
PMID:Intra- and interbacterial genetic exchange of Lyme disease spirochete erp genes generates sequence identity amidst diversity. 1462 41

The known genome sequence of Borrelia burgdorferi, an agent of Lyme borreliosis, was used to study the genetic content and gene expression in B. hermsii, another spirochete pathogen and a cause of relapsing fever. Cross-species hybridization of a DNA array representing 1628 open reading frames (ORF) of B. burgdorferi with genomic DNA of B. hermsii indicated that the latter organism has at least 81% of the chromosomal genes and 43% of the plasmid genes of B. burgdorferi. We then carried out quantitative hybridization of the arrays with multiple replicates of cDNA produced from B. hermsii cells growing in the blood of infected mice or in culture medium that was adjusted to the same pH, temperature and a spirochete density as infected blood. Of 642 B. burgdorferi ORFs hybridized by all replicates under both conditions, 12 (1.9%) demonstrated differential expression by a regularized t-test and stringent criteria. BBP07 and BBG30, two plasmid-borne ORFs with the greatest measurable difference in expression between in vivo and in vitro conditions, putatively encode proteins of unknown function. Orthologues of BBP07 in B. hermsii were identified, and increased expression in infected mice was demonstrated by quantitative reverse-transcriptase polymerase chain reaction.
Mol Microbiol 2004 Feb
PMID:Cross-species hybridization of a Borrelia burgdorferi DNA array reveals infection- and culture-associated genes of the unsequenced genome of the relapsing fever agent Borrelia hermsii. 1473 Dec 75

Lyme borreliosis is a systemic infection caused by the spirochaete Borrelia burgdorferi, which is transmitted by tick bites and maintained in a delicately balanced ecological cycle. Recent increases in the population densities of tick hosts, the abundance of ticks and the proximity of man to natural tick habitats have led to an escalating worldwide incidence of Lyme borreliosis, and nonspecific clinical manifestations have yielded significant misunderstanding of the disease. After entry, B. burgdorferi activates local inflammation, yet evades host defences and facilitates dissemination by potentially masquerading with host components such as plasmin and complement. The extent of tissue injury is determined by the aggressiveness of host inflammation and immunological reactions, as well as by genetic attributes of the spirochaete. The clinical presentation can be highly varied, including early manifestations that are limited to erythema migrans and ranging to disseminated infection with arthritis, carditis, cranial nerve palsy, peripheral neuropathy, meningitis, or other manifestations. Diagnostic tests have improved, but are unhelpful during certain stages of infection. Therapy varies depending on the degree of involvement, and recovery is usually rapid and complete. Post-treatment clinical manifestations in the absence of evidence for active infection are still poorly understood. The understanding of how B. burgdorferi survives in the environment and interacts with human and mammalian hosts has improved. However, further advances in prevention and therapy depend on continued investigation of the ecological risks and improved understanding of the pathobiology of this obligate bacterial parasite.
Expert Rev Mol Med 2004 Jan 19
PMID:Lyme borreliosis (Lyme disease): molecular and cellular pathobiology and prospects for prevention, diagnosis and treatment. 1498 14

The authors describe a microarray system for disease diagnosis based on antibody-antigen interactions. Either biotinylated antibodies or antigens are coupled via streptavidin linkers onto a gold surface. This platform has been used to establish recombinant antibody-antigen interactions and to detect specific IgM antibodies in sera of patients suspected of Lyme borreliosis. Therefore, this microarray system can be adapted for further applications.
Methods Mol Biol 2004
PMID:A streptavidin-biotin-based microarray platform for immunoassays. 1502 Jul 81

Borrelia burgdorferi, the aetiologic agent of Lyme disease, modulates gene expression in response to changes imposed by its arthropod vector and mammalian hosts. As reactive oxygen species (ROS) are known to vary in these environments, we asked how B. burgdorferi responds to oxidative stress. The B. burgdorferi genome encodes a PerR homologue (recently designated BosR) that represses the oxidative stress response in other bacteria, suggesting a similar function in B. burgdorferi. When we tested the sensitivity of B. burgdorferi to ROS, one clonal non-infectious B. burgdorferi isolate exhibited hypersensitivity to t-butyl hydroperoxide when compared with infectious B. burgdorferi and other non-infectious isolates. Sequence analysis indicated that the hypersensitive non-infectious isolates bosR allele contained a single nucleotide substitution, converting an arginine to a lysine (bosRR39K). Mutants in bosRR39K exhibited an increase in resistance to oxidative stressors when compared with the parental non-infectious strain, suggesting that BosRR39K functioned as a repressor. Complementation with bosRR39K and bosR resulted in differential sensitivity to t-butyl hydroperoxide, indicating that these alleles are functionally distinct. In contrast to BosR, BosRR39K did not activate transcription of a napA promoter-lacZ reporter in Escherichia coli nor bind the napA promoter/operator domain. However, we found that both BosR and BosRR39K bound to the putative promoter/operator region of superoxide dismutase (sodA). In addition, we determined that cells lacking BosRR39K synthesized fourfold greater levels of the decorin binding adhesin DbpA suggesting that BosRR39K regulates genes unrelated to oxidative stress. Based on these data, we propose that the single amino acid substitution, R39K, dramatically alters the activity of BosR by altering its ability to bind DNA at target regulatory sequences.
Mol Microbiol 2004 Dec
PMID:A conservative amino acid change alters the function of BosR, the redox regulator of Borrelia burgdorferi. 1555 74

Borrelia burgdorferi, a spirochete transmitted to human hosts during feeding of infected Ixodes ticks, is the causative agent of Lyme disease. Serum-resistant B. burgdorferi strains cause a chronic, multisystemic form of the disease and bind complement factor H (FH) and FH-like protein 1 (FHL-1) on the spirochete surface. Here we report the atomic structure for the key FHL-1- and FH-binding protein BbCRASP-1 and reveal a homodimer that presents a novel target for drug design.
Nat Struct Mol Biol 2005 Mar
PMID:A novel fold for the factor H-binding protein BbCRASP-1 of Borrelia burgdorferi. 1571 64

Lyme disease is a tick-transmitted inflammatory disorder, caused by the spirochete Borrelia burgdorferi (Bb). Recent discoveries cast new light on Bb dissemination and the ensuing pathogenesis of inflammation. Although the strong proinflammatory Bb lipoproteins have been implicated in the induction of inflammation, they do not seem to act exclusively through Toll-like receptor (TLR) engagement. In fact, mice that are deficient for MyD88, a component of the TLR signaling pathway, manifest similar or increased recruitment of cells into Bb-infected tissues. By contrast, the absence of the chemokine receptor CXCR2 results in reduced inflammation. Overall, these findings highlight the complexity of Lyme disease pathogenesis and identify chemokine pathways as novel therapeutic targets for the control of Bb-induced inflammation.
Trends Mol Med 2005 Mar
PMID:Chemokines and Toll-like receptors in Lyme disease pathogenesis. 1576 Jul 69

Spirochetes of the genus Borrelia include the causative agents of Lyme disease and relapsing fever. These bacteria have a highly segmented genome where most replicons are linear molecules terminated by covalently closed hairpin telomeres. Moreover, these genomes appear to be in a state of flux with extensive and ongoing DNA rearrangements by unknown mechanisms. The B. burgdorferi telomere resolvase ResT generates the hairpin telomeres from replication intermediates in a reaction with mechanistic similarities to that catalyzed by type IB topoisomerases and tyrosine recombinases. We report here the unexpected ability of ResT to catalyze the fusion of hairpin telomeres in a reversal of the telomere resolution reaction. We propose that stabilized ResT-mediated telomere fusions are an underlying force for maintaining the B. burgdorferi genome in a state of flux.
Mol Cell 2005 Mar 18
PMID:Fusion of hairpin telomeres by the B. burgdorferi telomere resolvase ResT implications for shaping a genome in flux. 1578 Sep 35


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