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Frontiers in Cellular and Infection... 2013Borrelia burgdorferi (Bb) is the causative agent of Lyme disease transmitted to humans by ticks of the Ixodes spp. Bb is a unique bacterial pathogen because it does not... (Review)
Review
Borrelia burgdorferi (Bb) is the causative agent of Lyme disease transmitted to humans by ticks of the Ixodes spp. Bb is a unique bacterial pathogen because it does not require iron (Fe(2+)) for its metabolism. Bb encodes a ferritin-like Dps homolog called NapA (also called BicA), which can bind Fe or copper (Cu(2+)), and a manganese (Mn(2+)) transport protein, Borrelia metal transporter A (BmtA); both proteins are required for colonization of the tick vector, but BmtA is also required for the murine host. This demonstrates that Bb's metal homeostasis is a critical facet of the complex enzootic life cycle between the arthropod and murine hosts. Although metals are known to influence the expression of virulence determinants during infection, it is unknown how or if metals regulate virulence in Bb. Recent evidence demonstrates that Bb modulates the intracellular Mn(2+) and zinc (Zn(2+)) content and, in turn, these metals regulate gene expression through influencing the Ferric Uptake Regulator (Fur) homolog Borrelia Oxidative Stress Regulator (BosR). This mini-review focuses on the burgeoning study of metal-dependent gene regulation within Bb.
Topics: Animals; Borrelia burgdorferi; Gene Expression Regulation, Bacterial; Homeostasis; Humans; Ixodes; Metals; Mice
PubMed: 24298449
DOI: 10.3389/fcimb.2013.00079 -
PloS One 2017RecA plays key roles in DNA recombination, replication and repair. Mutation of recA in the Lyme disease spirochete, Borrelia burgdorferi, fails to produce some of the...
RecA plays key roles in DNA recombination, replication and repair. Mutation of recA in the Lyme disease spirochete, Borrelia burgdorferi, fails to produce some of the phenotypes expected from study of recA mutation in other organisms. 'Missing' recA phenotypes include a lack of growth or viability effects, including in the presence of DNA damage, and a lack of a role in vlsE antigenic variation and infectivity. We present a purification and biochemical characterization of recombinant B. burgdorferi RecA protein. We find that B. burgdorferi RecA displays the expected properties of being a DNA-dependent ATPase, of having an intrinsic binding preference for ssDNA over dsDNA enhanced by ATP binding, of promoting DNA pairing and strand exchange reactions and of having a detectable coprotease activity with E. coli LexA repressor. DNA pairing and strand exchange reactions promoted by B. burgdorferi RecA show an unusually strong dependence upon the presence of the cognate ssDNA binding protein (SSB) but are very sensitive to inhibition by SSB when the ssDNA was prebound by SSB. This indicates B. burgdorferi RecA may have an enhanced requirement for recombinational mediators to promote RecA-SSB exchange, despite the absence of homologues of the RecF pathway proteins that normally play this role in eubacteria. Finally, we do not find any unusual, intrinsic properties of B. burgdorferi's RecA protein to explain the unusual phenotype of recA mutation and suggest that there may be alternative recombinase functions that could explain the 'missing' phenotypes.
Topics: Adenosine Triphosphate; Borrelia burgdorferi; Hydrolysis; Rec A Recombinases
PubMed: 29088268
DOI: 10.1371/journal.pone.0187382 -
Scientific Reports Mar 2019Lyme borreliosis is the most common vector-borne zoonosis in the northern hemisphere, and the pathogens causing Lyme borreliosis have distinct, incompletely described...
Lyme borreliosis is the most common vector-borne zoonosis in the northern hemisphere, and the pathogens causing Lyme borreliosis have distinct, incompletely described transmission cycles involving multiple host groups. The mammal community in Fennoscandia differs from continental Europe, and we have limited data on potential competent and incompetent hosts of the different genospecies of Borrelia burgdorferi sensu lato (sl) at the northern distribution ranges where Lyme borreliosis is emerging. We used qPCR to determine presence of B. burgdorferi sl in tissue samples (ear) from 16 mammalian species and questing ticks from Norway, and we sequenced the 5S-23 S rDNA intergenic spacer region to determine genospecies from 1449 qPCR-positive isolates obtaining 423 sequences. All infections coming from small rodents and shrews were linked to the genospecies B. afzelii, while B. burgdorferi sensu stricto (ss) was only found in red squirrels (Sciurus vulgaris). Red squirrels were also infected with B. afzelii and B. garinii. There was no evidence of B. burgdorferi sl infection in moose (Alces alces), red deer (Cervus elaphus) or roe deer (Capreolus capreolus), confirming the role of cervids as incompetent hosts. In infected questing ticks in the two western counties, B. afzelii (67% and 75%) dominated over B. garinii (27% and 21%) and with only a few recorded B. burgdorferi ss and B. valaisiana. B. burgdorferi ss were more common in adult ticks than in nymphs, consistent with a reservoir in squirrels. Our study identifies potential competent hosts for the different genospecies, which is key to understand transmission cycles at high latitudes of Europe.
Topics: Animals; Borrelia burgdorferi; Deer; Europe; Lyme Disease; Mammals; Norway; Polymerase Chain Reaction; Prevalence; Rodentia; Shrews; Ticks
PubMed: 30911054
DOI: 10.1038/s41598-019-41686-0 -
Infection and Immunity Nov 2020During the natural enzootic life cycle of (also known as ), the bacteria must sense conditions within the vertebrate and arthropod and appropriately regulate expression...
During the natural enzootic life cycle of (also known as ), the bacteria must sense conditions within the vertebrate and arthropod and appropriately regulate expression of genes necessary to persist within these distinct environments. of encodes a hypothetical protein of unknown function that is predicted to contain an N-terminal helix-turn-helix (HTH) domain. Because HTH domains can mediate protein-DNA interactions, we hypothesized that BB0345 might represent a previously unidentified borrelial transcriptional regulator with the ability to regulate events critical for the enzootic cycle. To study the role of BB0345 within mammals, we generated a mutant and assessed its virulence potential in immunocompetent mice. The mutant was able to initiate localized infection and disseminate to distal tissues but was cleared from all sites by 14 days postinfection. growth curve analyses revealed that the mutant grew similar to wild-type bacteria in standard Barbour-Stoenner-Kelley II (BSK-II) medium; however, the mutant was not able to grow in dilute BSK-II medium or dialysis membrane chambers (DMCs) implanted in rats. Proteinase K accessibility assays and whole-cell partitioning indicated that BB0345 was intracellular and partially membrane associated. Comparison of protein production profiles between the wild-type parent and the mutant revealed no major differences, suggesting BB0345 may not be a global transcriptional regulator. Taken together, these data show that BB0345 is essential for survival in the mammalian host, potentially by aiding the spirochete with a physiological function that is required by the bacterium during infection.
Topics: Animals; Bacterial Proteins; Borrelia burgdorferi; Computational Biology; Female; Gene Expression Regulation, Bacterial; Host Microbial Interactions; Lipoproteins; Lyme Disease; Membrane Proteins; Mice; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Spirochaetales
PubMed: 32928963
DOI: 10.1128/IAI.00472-20 -
MBio Dec 2017is an extreme amino acid (AA) auxotroph whose genome encodes few free AA transporters and an elaborate oligopeptide transport system ( Opp [Opp]). Opp consists of five...
is an extreme amino acid (AA) auxotroph whose genome encodes few free AA transporters and an elaborate oligopeptide transport system ( Opp [Opp]). Opp consists of five oligopeptide-binding proteins (OBPs), two heterodimeric permeases, and a heterodimeric nucleotide-binding domain (NBD). Homology modeling based on the crystal structure of liganded OppA4 revealed that each OBP likely binds a distinct range of peptides. Transcriptional analyses demonstrated that the OBPs are differentially and independently regulated whereas the permeases and NBDs are constitutively expressed. A conditional NBD mutant failed to divide in the absence of inducer and replicated in an IPTG (isopropyl-β-d-thiogalactopyranoside) concentration-dependent manner. NBD mutants grown without IPTG exhibited an elongated morphotype lacking division septa, often with flattening at the cell center due to the absence of flagellar filaments. Following cultivation in dialysis membrane chambers, NBD mutants recovered from rats not receiving IPTG also displayed an elongated morphotype. The NBD mutant was avirulent by needle inoculation, but infectivity was partially restored by oral administration of IPTG to infected mice. We conclude that peptides are a major source of AAs for both and and that peptide uptake is essential for regulation of morphogenesis, cell division, and virulence., the causative agent of Lyme disease, is an extreme amino acid (AA) auxotroph with a limited repertoire of annotated single-AA transporters. A major issue is how the spirochete meets its AA requirements as it transits between its arthropod vector and mammalian reservoir. While previous studies have confirmed that the oligopeptide transport () system is capable of importing peptides, the importance of the system for viability and pathogenesis has not been established. Here, we evaluated the system structurally and transcriptionally to elucidate its ability to import a wide range of peptides during the spirochete's enzootic cycle. Additionally, using a novel mutagenesis strategy to abrogate transporter function, we demonstrated that peptide uptake is essential for bacterial viability, morphogenesis, and infectivity. Our studies revealed a novel link between borrelial physiology and virulence and suggest that peptide uptake serves an intracellular signaling function regulating morphogenesis and division.
Topics: Animals; Borrelia burgdorferi; Disease Models, Animal; Gene Expression Regulation, Bacterial; Lyme Disease; Membrane Transport Proteins; Mice, Inbred C3H; Microbial Viability; Models, Molecular; Oligopeptides; Protein Conformation; Virulence
PubMed: 29259089
DOI: 10.1128/mBio.02047-17 -
Infection and Immunity Sep 2012Borrelia burgdorferi is the tick-borne bacterium that causes the multistage inflammatory disease Lyme disease. B. burgdorferi has a reduced genome and lacks the enzymes...
Borrelia burgdorferi is the tick-borne bacterium that causes the multistage inflammatory disease Lyme disease. B. burgdorferi has a reduced genome and lacks the enzymes required for de novo synthesis of purines for synthesis of RNA and DNA. Therefore, this obligate pathogen is dependent upon the tick vector and mammalian host environments for salvage of purine bases for nucleic acid biosynthesis. This pathway is vital for B. burgdorferi survival throughout its infectious cycle, as key enzymes in the purine salvage pathway are essential for the ability of the spirochete to infect mice and critical for spirochete replication in the tick. The transport of preformed purines into the spirochete is the first step in the purine salvage pathway and may represent a novel therapeutic target and/or means to deliver antispirochete molecules to the pathogen. However, the transport systems critical for purine salvage by B. burgdorferi have yet to be identified. Herein, we demonstrate that the genes bbb22 and bbb23, present on B. burgdorferi's essential plasmid circular plasmid 26 (cp26), encode key purine transport proteins. BBB22 and/or BBB23 is essential for hypoxanthine transport and contributes to the transport of adenine and guanine. Furthermore, B. burgdorferi lacking bbb22-23 was noninfectious in mice up to a dose of 1 × 10(7) spirochetes. Together, our data establish that bbb22-23 encode purine permeases critical for B. burgdorferi mammalian infectivity, suggesting that this transport system may serve as a novel antimicrobial target for the treatment of Lyme disease.
Topics: Adenine; Animals; Borrelia burgdorferi; Disease Models, Animal; Female; Guanine; Hypoxanthine; Lyme Disease; Membrane Transport Proteins; Mice; Mice, Inbred C3H; Plasmids; Virulence Factors
PubMed: 22710875
DOI: 10.1128/IAI.00514-12 -
PloS One 2016In China, B. burgdorferi, B.garinii, B. afzelii and B. yangtze sp. nov have been reported; B.garinii and B. afzelii are the main pathogenic genotypes. But until now only...
In China, B. burgdorferi, B.garinii, B. afzelii and B. yangtze sp. nov have been reported; B.garinii and B. afzelii are the main pathogenic genotypes. But until now only one Chinese strain was reported with whole genome sequence. In order to further understand the genomic characteristics and diversity of Chinese Borrelia strains, 5 isolates from China were sequenced and compared with the whole genome sequences of strains in other areas. The results showed a high degree of conservation within the linear chromosome of Chinese strains, whereas plasmid showed a much larger diversity according to the majority genomic information of plasmids. The genome sequences of the five Chinese strains were compared with the corresponding reference strains, respectively, according to the genospecies. Pairwise analysis demonstrates that there are only 70 SNPs between the genomes of CS4 and B31. However, there are many more SNPs between the genomes of QX-S13 and VS116, PD91 and PBi, FP1 and PKo, R9 and Pko, respectively. Gene comparison showed some important different genes. OspA was one of the important different genes. Comparative genomic studies have found that OspA gene sequences of PD91 and R9 had great differences compared with the sequence of B31. OspA gene sequence of R9 had a 96bp deletion; OspA gene of PD91 had two deletions: 9bp and 10 bp. To conclude, we showed the genomic characteristics of four genotype Chinese B. burgdorferi strains. The genomic sequence of B. yangtze sp. nov and differences from B. valaisiana were first reported. Comparative analysis of Chinese strains with the different Borrelia species from other areas will help us to understand evolution and pathogenesis of Chinese Borrelia burgdorferi strains.
Topics: Borrelia burgdorferi; China; DNA, Bacterial; Genes, Bacterial; Genome, Bacterial; Genomics; Genotype; Plasmids; Polymorphism, Single Nucleotide; Sequence Analysis, DNA
PubMed: 27093540
DOI: 10.1371/journal.pone.0153149 -
MBio Sep 2019A detailed first-hand account of the events leading up to the discovery of the Lyme disease agent has been lacking. Nearly 40 years have elapsed since the discovery of...
A detailed first-hand account of the events leading up to the discovery of the Lyme disease agent has been lacking. Nearly 40 years have elapsed since the discovery of the organism that was named There are thousands of articles in the scientific and medical literature on this organism and the disease that it causes. In the interval since the organism's discovery, however, misconceptions have arisen regarding not only the disease but the discovery itself. Accordingly, with this paper, we aim to fill in the details of this episode in medical history with a joint introduction, first-person accounts by the two authors, a summary of contemporaneous events, and concluding comments. The history of the discovery of the Lyme disease agent has threads originating in different places in the United States. Studies on Long Island, NY, provided the epidemiological thread of studies on rickettsial diseases and babesiosis, linking the latter with the cutaneous manifestation of Lyme disease, now known as erythema migrans. The Long Island thread intersected Montana's Rocky Mountain Laboratories thread of studies on a relapsing fever and its cultivation and expertise in vector biology. This intersection made possible the discovery of the spirochete and its recovery from patients. This paper stresses that what may seem to have been an individual scientific discovery is actually the product of several threads coming together and is attributable to more people than appreciated.
Topics: Animals; Borrelia burgdorferi; History, 20th Century; Humans; Ixodes; Lyme Disease; United States
PubMed: 31530679
DOI: 10.1128/mBio.02166-19 -
Biochemical and Biophysical Research... Aug 2020The causative agent of Lyme disease, Borrelia burgdorferi, requires shifts in gene expression to undergo its natural enzootic cycle between tick and vertebrate hosts....
The causative agent of Lyme disease, Borrelia burgdorferi, requires shifts in gene expression to undergo its natural enzootic cycle between tick and vertebrate hosts. mRNA decay mechanisms play significant roles in governing gene expression in other bacteria, but are not yet characterized in B. burgdorferi. RNase III is an important enzyme in processing ribosomal RNA, but it also plays a role in mRNA decay in many bacteria. We compared RNA decay profiles and steady-state abundances of transcripts in wild-type Borrelia burgdorferi strain B31 and in an RNase III null (rnc) mutant. Transcripts encoding RNA polymerase subunits (rpoA and rpoS), ribosomal proteins (rpsD, rpsK, rpsM, rplQ, and rpsO), a nuclease (pnp), a flagellar protein (flaB), and a translational regulator (bpuR) decayed more rapidly in the wild-type strain than in the slow growing rnc mutant indicating that RNA turnover is mediated by RNase III in the bacterium that causes Lyme disease. Additionally, in wild type bacteria, RNA decay rates of rpoS, rpoN, ospA, ospC, bpuR and dbpA transcripts are only modestly affected by changes in the osmolarity.
Topics: Animals; Bacterial Proteins; Borrelia burgdorferi; Gene Deletion; Gene Expression Regulation, Bacterial; Humans; Lyme Disease; RNA Stability; RNA, Messenger; Ribonuclease III
PubMed: 32703440
DOI: 10.1016/j.bbrc.2020.05.201 -
Annual Review of Microbiology 2012Spirochete motility is enigmatic: It differs from the motility of most other bacteria in that the entire bacterium is involved in translocation in the absence of... (Review)
Review
Spirochete motility is enigmatic: It differs from the motility of most other bacteria in that the entire bacterium is involved in translocation in the absence of external appendages. Using the Lyme disease spirochete Borrelia burgdorferi (Bb) as a model system, we explore the current research on spirochete motility and chemotaxis. Bb has periplasmic flagella (PFs) subterminally attached to each end of the protoplasmic cell cylinder, and surrounding the cell is an outer membrane. These internal helix-shaped PFs allow the spirochete to swim by generating backward-moving waves by rotation. Exciting advances using cryoelectron tomography are presented with respect to in situ analysis of cell, PF, and motor structure. In addition, advances in the dynamics of motility, chemotaxis, gene regulation, and the role of motility and chemotaxis in the life cycle of Bb are summarized. The results indicate that the motility paradigms of flagellated bacteria do not apply to these unique bacteria.
Topics: Borrelia burgdorferi; Chemotaxis; Flagella; Locomotion
PubMed: 22994496
DOI: 10.1146/annurev-micro-092611-150145