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The spirochete Borrelia burgdorferi, the etiologic agent of Lyme disease, causes severe subacute arthritis in susceptible inbred mouse strains, such as C3H/HeN, but only mild arthritis in resistant strains such as C57BL/6. The degree of Lyme arthritis severity is controlled in part by host genetics and several quantitative trait loci have been identified which contribute to this regulation. In addition, the anti-inflammatory cytokine IL-10 assumes an important role in the control of arthritis in C57BL/6 mice. However, the identification of genes and signaling pathways that dictate arthritis severity has remained elusive. In an attempt to elucidate such genes and pathways, the power of microarray analysis was combined with information gleaned from gene manipulation models. As a result of this approach, two novel gene profiles were identified: an IFN-inducible profile in arthritis-susceptible C3H and IL-10(-/-) mice, and an epidermal/differentiation profile in C57BL/6 mice. Application of this information to TLR2(-/-) mice, which also develop severe arthritis, indicated that they also upregulated IFN-responsive genes. These results provided new insight into the regulation of Lyme arthritis development and illustrated the utility of combining gene expression analyses with genetically manipulated mouse models in unraveling mechanisms underlying specific disease processes.
Exp Mol Pathol 2008 Aug
PMID:Gene expression profiling provides insights into the pathways involved in inflammatory arthritis development: murine model of Lyme disease. 1846 18

Borrelia burgdorferi, the causative agent of Lyme disease, has a limited set of genes to combat oxidative/nitrosative stress encountered in its tick vector or mammalian hosts. We inactivated the gene encoding for superoxide dismutase A (sodA, bb0153), an enzyme mediating the dismutation of superoxide anions and examined the in vitro and in vivo phenotype of the mutant. There were no significant differences in the in vitro growth characteristics of the sodA mutant compared with the control strains. Microscopic analysis of viability of spirochaetes revealed greater percentage of cell death upon treatment of sodA mutant with superoxide generators compared with its controls. Infectivity analysis in C3H/HeN mice following intradermal needle inoculation of 10(3) or 10(5) spirochaetes per mouse revealed complete attenuation of infectivity for the sodA mutant compared with control strains at 21 days post infection. The sodA mutant was more susceptible to the effects of activated macrophages and neutrophils, suggesting that its in vivo phenotype is partly due to the killing effects of activated immune cells. These studies indicate that SodA plays an important role in combating oxidative stress and is essential for the colonization and dissemination of B. burgdorferi in the murine model of Lyme disease.
Mol Microbiol 2009 Feb
PMID:sodA is essential for virulence of Borrelia burgdorferi in the murine model of Lyme disease. 1904 Jun 38

When taking their blood meal on the mammalian host, ticks transfer a multitude of different proteins from their saliva into the host. Some of these proteins are hijacked by pathogens for their own purposes. Borrelia burgdorferi, the Lyme disease agent, is critically dependent on the presence of the tick protein Salp15 when infecting the host. Similarly, Anaplasma phagocytophilum, which causes anaplasmosis, needs Salp16, a homologue of Salp15, to get transferred from the host into the tick. Here we analyzed whether adaptive evolution has shaped the Salp15 protein family. Using site-specific estimates of K(A)/K(S) ratios, we identified different positions within the Salp15 protein family which have undergone a phase of positive selection. Additionally, we analyzed the B. burgdorferi protein interacting with Salp15, OspC. Again, sites showing signs of positive selection were identified, although they are more likely a result of the antigenic features of OspC than of the influence of Salp15. The identification of probably functionally relevant sites in the Salp15 family might direct the detailed experimental analysis of their interaction with human and bacterial proteins.
J Mol Evol 2009 Feb
PMID:Positive selection in tick saliva proteins of the Salp15 family. 1915 66

Spirochetes of the genus Borrelia include the causative agents of Lyme disease and relapsing fever. They possess unusual, highly segmented genomes composed mostly of linear replicons with covalently closed hairpin telomeres. The telomeres are formed from inverted repeat replicated telomere junctions (rTels) by the telomere resolvase, ResT. ResT uses a reaction mechanism with similarities to that employed by the type IB topoisomerases and tyrosine recombinases. Here, we report that the relationship of ResT to the tyrosine recombinases extends to the ability to synapse-replicated telomeres and to catalyse the formation of a Holliday junction. We also report that ResT can use asymmetrized substrates that mimic the properties of a recombination site for a tyrosine recombinase, to form Holliday junctions. We propose a model for how this explains the origin of genome linearity in the genus Borrelia.
Mol Microbiol 2009 Mar
PMID:Holliday junction formation by the Borrelia burgdorferi telomere resolvase, ResT: implications for the origin of genome linearity. 1917 Aug 85

Spirochetes of the Borrelia burgdorferi sensu lato group, the causative agents of Lyme borreliosis, exhibit a complex biology evolved in its zoonotic cycle. Cryo-electron tomography was used to investigate structural features of three species, B. burgdorferi, B. garinii and B. afzelii, known to cause different clinical manifestations in humans. All three organisms revealed an overall similar architecture and showed different numbers of periplasmic flagellar filaments, polar periplasmic void regions, vesicles budding from the outer membrane sheath, which was covered by an amorphous slime layer. The latter was shown to be distinct in its density when comparing the three human-pathogenic Lyme disease spirochetes and Borrelia hermsii, a species causing relapsing fever. Tomograms of dividing bacteria revealed vesicles near the site of division and new basal bodies that were attached at each end of newly establishing cytoplasmic cylinder poles, while periplasmic flagellar filaments still passed the impending site of division. Two different kinds of cytoplasmic filaments showed similarities to MreB or FtsZ filaments of other bacteria. The similar and distinct structural features of Borrelia and the previously investigated pathogenic and non-pathogenic Treponema species emphasize the importance of further studying phylogenetically distant spirochetes.
Mol Microbiol 2009 Mar
PMID:Comparative cryo-electron tomography of pathogenic Lyme disease spirochetes. 1921 Jun 19

Two-component systems (TCS) are universal among bacteria and play critical roles in gene regulation. Our understanding of the contributions of TCS in the biology of the Borrelia is just now beginning to develop. Borrelia burgdorferi, a causative agent of Lyme disease, harbours a TCS comprised of open reading frames (ORFs) BB0419 and BB0420. BB0419 encodes a response regulator designated Rrp1, and BB0420 encodes a hybrid histidine kinase-response regulator designated Hpk1. Rrp1, which contains a conserved GGDEF domain, undergoes phosphorylation and produces the secondary messenger, cyclic diguanylate (c-di-GMP), a critical signaling molecule in numerous organisms. However, the regulatory role of the Rrp1-Hpk1 TCS and c-di-GMP signaling in Borrelia biology are unexplored. In this study, the distribution, conservation, expression and potential global regulatory capability of Rrp1 were assessed. rrp1 was found to be universal and highly conserved among isolates, co-transcribed with hpk1, constitutively expressed during in vitro cultivation, and significantly upregulated upon tick feeding. Allelic exchange replacement and microarray analyses revealed that the Rrp1 regulon consists of a large number of genes encoded by the core Borrelia genome (linear chromosome, linear plasmid 54 and circular plasmid 26) that encode for proteins involved in central metabolic processes and virulence mechanisms including immune evasion.
Mol Microbiol 2009 Mar
PMID:Rrp1, a cyclic-di-GMP-producing response regulator, is an important regulator of Borrelia burgdorferi core cellular functions. 1921 Jun 21

Analysis of natural selection is key to understanding many core biological processes, including the emergence of competition, cooperation, and complexity, and has important applications in the targeted development of vaccines. Selection is hard to observe directly but can be inferred from molecular sequence variation. For protein-coding nucleotide sequences, the ratio of nonsynonymous to synonymous substitutions (omega) distinguishes neutrally evolving sequences (omega = 1) from those subjected to purifying (omega < 1) or positive Darwinian (omega > 1) selection. We show that current models used to estimate omega are substantially biased by naturally occurring sequence compositions. We present a novel model that weights substitutions by conditional nucleotide frequencies and which escapes these artifacts. Applying it to the genomes of pathogens causing malaria, leprosy, tuberculosis, and Lyme disease gave significant discrepancies in estimates with approximately 10-30% of genes affected. Our work has substantial implications for how vaccine targets are chosen and for studying the molecular basis of adaptive evolution.
Mol Biol Evol 2010 Mar
PMID:Estimates of the effect of natural selection on protein-coding content. 1981 89

Summary Borrelia burgdorferi (Bb), the Lyme disease spirochaete, encodes a potential ferric uptake regulator (Fur) homologue, BosR (BB0647). Thus far, a role for BosR in Bb metabolism, gene regulation or pathogenesis has not been determined, largely due to the heretofore inability to inactivate bosR in low-passage, infectious Bb isolates. Herein, we report the generation of the first bosR-deficient mutant in a virulent strain of Bb. Whereas the bosR mutant persisted normally in ticks, the mutant was unable to infect mice, indicating that BosR is essential for Bb infection of a mammalian host. Moreover, transcriptional profiling of the bosR mutant showed that a number of genes were either positively or negatively influenced by BosR deficiency, suggesting that BosR may function both as a global repressor and activator in Bb. Strikingly, our study showed that BosR controls the expression of two major virulence-associated Bb lipoproteins, OspC and DbpA, likely via an influence on the alternative sigma factor, RpoS. This study thus not only has elucidated another key virulence gene of Bb, but also provides new insights into a previously unknown layer of gene regulation governing RpoS in Bb.
Mol Microbiol 2009 Dec
PMID:BosR (BB0647) governs virulence expression in Borrelia burgdorferi. 1994 96

Summary Borrelia burgdorferi, the Lyme disease spirochete, adapts as it moves between the arthropod and mammalian hosts that it infects. We hypothesize that BosR serves as a global regulator in B. burgdorferi to modulate the oxidative stress response and adapt to mammalian hosts. To test this hypothesis, a bosR mutant in a low-passage B. burgdorferi isolate was constructed. The resulting bosR::kan(R) strain was altered when grown microaerobically or anaerobically suggesting that BosR is required for optimal replication under both growth conditions. The absence of BosR increased the sensitivity of B. burgdorferi to hydrogen peroxide and reduced the synthesis of Cdr and NapA, proteins important for cellular redox balance and the oxidative stress response, respectively, suggesting an important role for BosR in borrelial oxidative homeostasis. For the bosR mutant, the production of RpoS was abrogated and resulted in the loss of OspC and DbpA, suggesting that BosR interfaces with the Rrp2-RpoN-RpoS regulatory cascade. Consistent with the linkage to RpoS, cells lacking bosR were non-infectious in the mouse model of infection. These results indicate that BosR is required for resistance to oxidative stressors and provides a regulatory response that is necessary for B. burgdorferi pathogenesis.
Mol Microbiol 2009 Dec
PMID:The BosR regulatory protein of Borrelia burgdorferi interfaces with the RpoS regulatory pathway and modulates both the oxidative stress response and pathogenic properties of the Lyme disease spirochete. 1994 96

Borrelia burgdorferi encodes a novel DNA-binding protein in the Fur/PerR family of transcriptional regulators termed BosR (BB0647). This issue of Molecular Microbiology contains two molecular genetic studies that help to clarify the function of BB0647 and resolve longstanding controversies. Loss of BB0647 appears to have a pronounced effect on borrelial gene expression and, in one study, caused significant in vitro growth defects. BB0647 was also found to be essential for infection of the mammalian host but not the tick vector. Both Ouyang et al. and Hyde et al. also demonstrate, quite unexpectedly, that BB0647 is required for induction of RpoS, an alternative sigma factor that controls a cadre of B. burgdorferi genes, most notably ospC, which enable the spirochetes to establish mammalian infection following tick inoculation. There are still many unanswered questions regarding the precise physiological role of BB0647, the most important of which relate to its homologues Fur and PerR: to what extent does it regulate either the response to oxidative stress and/or transition metal uptake? The mechanism(s) whereby BB0647 interfaces with the Rrp2-RpoN-RpoS pathway also remains to be discerned. However, these two seminal papers establish BB0647 (BosR) as a central player in the molecular biology and physiology of B. burgdorferi as well as the pathogenesis of Lyme disease.
Mol Microbiol 2009 Dec
PMID:Who is the BosR around here anyway? 1990 79


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