scholarly journals The Relapsing Fever Spirochete Borrelia hermsiiContains Multiple, Antigen-Encoding Circular Plasmids That Are Homologous to the cp32 Plasmids of Lyme Disease Spirochetes

2000 ◽  
Vol 68 (7) ◽  
pp. 3900-3908 ◽  
Author(s):  
Brian Stevenson ◽  
Stephen F. Porcella ◽  
Katrina L. Oie ◽  
Cecily A. Fitzpatrick ◽  
Sandra J. Raffel ◽  
...  
Keyword(s):  
Lyme Disease ◽  
Direct Detection ◽  
Human Infection ◽  
Relapsing Fever ◽  
Borrelia Hermsii ◽  
Functional Studies ◽  
Dna Library ◽  
Multiple Antigen ◽  
Antigenic Proteins

ABSTRACT Borrelia hermsii, an agent of tick-borne relapsing fever, was found to contain multiple circular plasmids approximately 30 kb in size. Sequencing of a DNA library constructed from circular plasmid fragments enabled assembly of a composite DNA sequence that is homologous to the cp32 plasmid family of the Lyme disease spirochete,B. burgdorferi. Analysis of another relapsing fever bacterium, B. parkeri, indicated that it contains linear homologs of the B. hermsii and B. burgdorfericp32 plasmids. The B. hermsii cp32 plasmids encode homologs of the B. burgdorferi Mlp and Bdr antigenic proteins and BlyA/BlyB putative hemolysins, but homologs of B. burgdorferi erp genes were absent. Immunoblot analyses demonstrated that relapsing fever patients produced antibodies to Mlp proteins, indicating that those proteins are synthesized by the spirochetes during human infection. Conservation of cp32-encoded genes in differentBorrelia species suggests that their protein products serve functions essential to both relapsing fever and Lyme disease spirochetes. Relapsing fever borreliae replicate to high levels in the blood of infected animals, permitting direct detection and possible functional studies of Mlp, Bdr, BlyA/BlyB, and other cp32-encoded proteins in vivo.

scholarly journals A new Borrelia on the block: Borrelia miyamotoi – a human health risk?

2019 ◽  
Vol 24 (18) ◽  
Author(s):  
Sally Cutler ◽  
Muriel Vayssier-Taussat ◽  
Agustín Estrada-Peña ◽  
Aleksandar Potkonjak ◽  
Andrei Daniel Mihalca ◽  
...  
Keyword(s):  
Lyme Disease ◽  
Human Health Risk ◽  
Case Series ◽  
Human Infection ◽  
Future Research ◽  
Borrelia Miyamotoi ◽  
Relapsing Fever ◽  
Pathogenic Potential ◽  
In Vivo Models

Background Borrelia miyamotoi clusters phylogenetically among relapsing fever borreliae, but is transmitted by hard ticks. Recent recognition as a human pathogen has intensified research into its ecology and pathogenic potential. Aims We aimed to provide a timely critical integrative evaluation of our knowledge on B. miyamotoi, to assess its public health relevance and guide future research. Methods This narrative review used peer-reviewed literature in English from January 1994 to December 2018. Results Borrelia miyamotoi occurs in the world’s northern hemisphere where it co-circulates with B. burgdorferi sensu lato, which causes Lyme disease. The two borreliae have overlapping vertebrate and tick hosts. While ticks serve as vectors for both species, they are also reservoirs for B. miyamotoi. Three B. miyamotoi genotypes are described, but further diversity is being recognised. The lack of sufficient cultivable isolates and vertebrate models compromise investigation of human infection and its consequences. Our understanding mainly originates from limited case series. In these, human infections mostly present as influenza-like illness, with relapsing fever in sporadic cases and neurological disease reported in immunocompromised patients. Unspecific clinical presentation, also occasionally resulting from Lyme- or other co-infections, complicates diagnosis, likely contributing to under-reporting. Diagnostics mainly employ PCR and serology. Borrelia miyamotoi infections are treated with antimicrobials according to regimes used for Lyme disease. Conclusions With co-infection of tick-borne pathogens being commonplace, diagnostic improvements remain important. Developing in vivo models might allow more insight into human pathogenesis. Continued ecological and human case studies are key to better epidemiological understanding, guiding intervention strategies.

scholarly journals In Vitro and In Vivo Neutralization of the Relapsing Fever Agent Borrelia hermsii with Serotype-Specific Immunoglobulin M Antibodies

2001 ◽  
Vol 69 (2) ◽  
pp. 1009-1015 ◽  
Author(s):  
Alan G. Barbour ◽  
Virgilio Bundoc
Keyword(s):  
Monoclonal Antibodies ◽  
Antibody Response ◽  
Immunoglobulin M ◽  
Enzyme Linked Immunosorbent Assay ◽  
Relapsing Fever ◽  
Borrelia Hermsii ◽  
Intact Cells ◽  
Whole Cells

ABSTRACT The antigenic variation of the relapsing fever agent Borrelia hermsii is associated with changes in the expression of the Vlp and Vsp outer membrane lipoproteins. To investigate whether these serotype-defining proteins are the target of a neutralizing and protective antibody response, monoclonal antibodies were produced from spleens of infected mice just after clearance of serotype 7 cells from the blood. Two immunoglobulin M monoclonal antibodies, H7-7 and H7-12, were studied in detail. Both antibodies specifically agglutinated serotype 7 cells and inhibited their growth in vitro. Administered to mice before or after infection, both antibodies provided protection against infection or substantially reduced the number of spirochetes in the blood of mice after infection. Whereas antibody H7-12 bound to Vlp7 in Western blotting, enzyme-linked immunosorbent assay, and immunoprecipitation assays, as well as to whole cells in other immunoassays, antibody H7-7 only bound to wet, intact cells of serotype 7. Antibody H7-7 selected against cells expressing Vlp7 in vitro and in vivo, an indication that Vlp7 was a conformation-sensitive antigen for the antibody. Vaccination of mice with recombinant Vlp7 with adjuvant elicited antibodies that bound to fixed whole cells of serotype 7 and to Vlp7 in Western blots, but these antibodies did not inhibit the growth of serotype 7 in vitro and did not provide protection against an infectious challenge with serotype 7. The study established that a Vlp protein was the target of a neutralizing antibody response, and it also indicated that the conformation and/or the native topology of Vlp were important for eliciting that immunity.

scholarly journals BBK07 Immunodominant Peptides as Serodiagnostic Markers of Lyme Disease

2010 ◽  
Vol 18 (3) ◽  
pp. 406-413 ◽  
Author(s):  
Adam S. Coleman ◽  
Evelyn Rossmann ◽  
Xiuli Yang ◽  
Haichen Song ◽  
Chinta M. Lamichhane ◽  
...  
Keyword(s):  
Lyme Disease ◽  
Bacterial Pathogen ◽  
Surface Protein ◽  
Human Infection ◽  
Full Length ◽  
Enzyme Linked Immunosorbent Assay ◽  
Lower Sensitivity ◽  
Serum Samples ◽  
Amino Terminal

ABSTRACTLyme disease (LD) is a tick-borne infection caused by the bacterial pathogenBorrelia burgdorferi. Current diagnostic tests mostly use borrelial lysates or select antigens to detect serum antibodies againstB. burgdorferi. These immunoassays are not entirely effective, especially for detection of early infection. We have recently characterized anin vivo-induced antigen, BBK07, as a serodiagnostic marker for LD. We now report that in a line blot assay, recombinant BBK07 protein-based detection is 90% sensitive and nearly 100% specific againstB. burgdorferiinfection in humans. Using an overlapping peptide library of 23 peptides encompassing full-length BBK07, we identified the immunodominant epitopes of BBK07 during human infection. We show that a select combination of amino-terminal peptides significantly enhanced BBK07-based diagnostic accuracy compared to that with the full-length protein. Although in enzyme-linked immunosorbent assay (ELISA) studies BBK07 peptides had overall lower sensitivity than established serodiagnostic peptides, such as the VlsE peptide C6 and OspC peptide pepC10, for the detection of early human LD, a subset of serum samples that failed to recognize either VlsE or OspC peptides were preferentially reactive to BBK07 peptides. These results highlight the fact that BBK07 peptides could be useful to complement the efficacy of VlsE and OspC peptide-based serodiagnostic assays. Finally, using a panel of canine sera, we show that BBK07 peptide is also effective for LD diagnosis in infected dogs. Together, our data show that peptides from theB. burgdorferisurface protein BBK07 are highly specific and sensitive serodiagnostic markers, and we suggest their future use in LD diagnostic assays.

scholarly journals Genetic Control of the Innate Immune Response to Borrelia hermsii Influences the Course of Relapsing Fever in Inbred Strains of Mice

2009 ◽  
Vol 78 (2) ◽  
pp. 586-594 ◽  
Author(s):  
Vivian M. Benoit ◽  
Annett Petrich ◽  
Kishore R. Alugupalli ◽  
Robin Marty-Roix ◽  
Annette Moter ◽  
...  
Keyword(s):  
Genetic Control ◽  
Inbred Strains ◽  
Human Infection ◽  
Host Susceptibility ◽  
Fish Analysis ◽  
Relapsing Fever ◽  
Large Measure ◽  
Borrelia Hermsii ◽  
Inbred Strains Of Mice ◽  
Wide Range

ABSTRACT Host susceptibility to infection is controlled in large measure by the genetic makeup of the host. Spirochetes of the genus Borrelia include nearly 40 species of vector-borne spirochetes that are capable of infecting a wide range of mammalian hosts, causing Lyme disease and relapsing fever. Relapsing fever is associated with high-level bacteremia, as well as hematologic manifestations, such as thrombocytopenia (i.e., low platelet numbers) and anemia. To facilitate studies of genetic control of susceptibility to Borrelia hermsii infection, we performed a systematic analysis of the course of infection using immunocompetent and immunocompromised inbred strains of mice. Our analysis revealed that sensitivity to B. hermsii infections is genetically controlled. In addition, whereas the role of adaptive immunity to relapsing fever-causing spirochetes is well documented, we found that innate immunity contributes significantly to the reduction of bacterial burden. Similar to human infection, the progression of the disease in mice was associated with thrombocytopenia and anemia. Histological and fluorescence in situ hybridization (FISH) analysis of infected tissues indicated that red blood cells (RBCs) were removed by tissue-resident macrophages, a process that could lead to anemia. Spirochetes in the spleen and liver were often visualized associated with RBCs, lending support to the hypothesis that direct interaction of B. hermsii spirochetes with RBCs leads to clearance of bacteria from the bloodstream by tissue phagocytes.

scholarly journals The Borrelia hermsii Factor H Binding Protein FhbA Is Not Required for Infectivity in Mice or for Resistance to Human ComplementIn Vitro

2014 ◽  
Vol 82 (8) ◽  
pp. 3324-3332 ◽  
Author(s):  
Lindy M. Fine ◽  
Daniel P. Miller ◽  
Katherine L. Mallory ◽  
Brittney K. Tegels ◽  
Christopher G. Earnhart ◽  
...  
Keyword(s):  
Genetic Manipulation ◽  
Binding Protein ◽  
Factor H ◽  
Negative Regulator ◽  
Human Complement ◽  
Relapsing Fever ◽  
Borrelia Hermsii ◽  
Content Type

ABSTRACTThe primary causative agent of tick-borne relapsing fever in North America isBorrelia hermsii. It has been hypothesized thatB. hermsiievades complement-mediated destruction by binding factor H (FH), a host-derived negative regulator of complement.In vitro,B. hermsiiproduces a single FH binding protein designated FhbA (FH binding protein A). The properties and ligand binding activity of FhbA suggest that it plays multiple roles in pathogenesis. It binds plasminogen and has been identified as a significant target of a B1b B cell-mediated IgM response in mice. FhbA has also been explored as a potential diagnostic antigen forB. hermsiiinfection in humans. The ability to test the hypothesis that FhbA is a critical virulence factorin vivohas been hampered by the lack of well-developed systems for the genetic manipulation of the relapsing fever spirochetes. In this report, we have successfully generated aB. hermsiifhbAdeletion mutant (theB. hermsiiYORΔfhbAstrain) through allelic exchange mutagenesis. Deletion offhbAabolished FH binding by the YORΔfhbAstrain and eliminated cleavage of C3b on the cell surface. However, the YORΔfhbAstrain remained infectious in mice and retained resistance to killingin vitroby human complement. Collectively, these results indicate thatB. hermsiiemploys an FhbA/FH-independent mechanism of complement evasion that allows for resistance to killing by human complement and persistence in mice.

scholarly journals Relapsing Fever Spirochetes Contain Chromosomal Genes with Unique Direct Tandemly Repeated Sequences

2005 ◽  
Vol 73 (5) ◽  
pp. 3025-3037 ◽  
Author(s):  
Cyril Guyard ◽  
Earl M. Chester ◽  
Sandra J. Raffel ◽  
Merry E. Schrumpf ◽  
Paul F. Policastro ◽  
...  
Keyword(s):  
Amino Acid ◽  
Human Infection ◽  
Amino Acid Sequences ◽  
Open Reading Frames ◽  
Relapsing Fever ◽  
Serum Samples ◽  
Borrelia Hermsii ◽  
Reading Frames ◽  
Antigenic Heterogeneity

ABSTRACT Genome sequencing of the relapsing fever spirochetes Borrelia hermsii and Borrelia turicatae identified three open reading frames (ORFs) on the chromosomes that contained internal, tandemly repeated amino acid sequences that were absent in the Lyme disease spirochete Borrelia burgdorferi. The predicted amino acid sequences of these genes (BH0209, BH0512, and BH0553) have hydrophobic N termini, indicating that these proteins may be secreted. B. hermsii transcribed the three ORFs in vitro, and the BH0512- and BH0553-encoded proteins (PBH-512 and PBH-553) were produced in vitro and in experimentally infected mice. PBH-512 and PBH-553 were on the spirochete's outer surface, and antiserum to these proteins reduced the adherence of B. hermsii to red blood cells. PCR analyses of 28 isolates of B. hermsii and 8 isolates of B. turicatae demonstrated polymorphism in each gene correlated with the number of repeats. Serum samples from relapsing fever patients reacted with recombinant PBH-512 and PBH-553, suggesting that these proteins are produced during human infection. These polymorphic proteins may be involved in the pathogenicity of these relapsing fever spirochetes and provide a mechanism for antigenic heterogeneity within their populations.

scholarly journals Single Core Genome Sequencing for Detection of both Borrelia burgdorferi Sensu Lato and Relapsing Fever Borrelia Species

2019 ◽  
Vol 16 (10) ◽  
pp. 1779
Author(s):  
Sin Hang Lee ◽  
John Eoin Healy ◽  
John S Lambert
Keyword(s):  
United States ◽  
Lyme Disease ◽  
16S Rrna ◽  
Borrelia Burgdorferi ◽  
Genome Sequencing ◽  
Core Genome ◽  
Direct Detection ◽  
Early Stage ◽  
The United States ◽  
Relapsing Fever

Lyme disease, initially described as Lyme arthritis, was reported before nucleic-acid based detection technologies were available. The most widely used diagnostic tests for Lyme disease are based on the serologic detection of antibodies produced against antigens derived from a single strain of Borrelia burgdorferi. The poor diagnostic accuracy of serological tests early in the infection process has been noted most recently in the 2018 Report to Congress issued by the U.S. Department of Health and Human Services Tick-Borne Disease Working Group. Clinical Lyme disease may be caused by a diversity of borreliae, including those classified as relapsing fever species, in the United States and in Europe. It is widely accepted that antibiotic treatment of Lyme disease is most successful during this critical early stage of infection. While genomic sequencing is recognized as an irrefutable direct detection method for laboratory diagnosis of Lyme borreliosis, development of a molecular diagnostic tool for all clinical forms of borreliosis is challenging because a “core genome” shared by all pathogenic borreliae has not yet been identified. After a diligent search of the GenBank database, we identified two highly conserved segments of DNA sequence among the borrelial 16S rRNA genes. We further developed a pair of Borrelia genus-specific PCR primers for amplification of a segment of borrelial 16S rRNA gene as a “core genome” to be used as the template for routine Sanger sequencing-based metagenomic direct detection test. This study presented examples of base-calling DNA sequencing electropherograms routinely generated in a clinical diagnostic laboratory on DNA extracts of human blood specimens and ticks collected from human skin bites and from the environment. Since some of the tick samples tested were collected in Ireland, borrelial species or strains not known to exist in the United States were also detected by analysis of this 16S rRNA “core genome”. We recommend that hospital laboratories located in Lyme disease endemic areas begin to use a “core genome” sequencing test to routinely diagnose spirochetemia caused by various species of borreliae for timely management of patients at the early stage of infection.

scholarly journals Comparative Analysis and Immunological Characterization of the Borrelia Bdr Protein Family

1999 ◽  
Vol 67 (7) ◽  
pp. 3257-3266 ◽  
Author(s):  
Wolfram R. Zückert ◽  
Jürg Meyer ◽  
Alan G. Barbour
Keyword(s):  
Lyme Disease ◽  
Disease Patient ◽  
Direct Repeat ◽  
Protein Family ◽  
Relapsing Fever ◽  
Independent Manner ◽  
Borrelia Hermsii ◽  
Western Blots ◽  
Disease Analysis

ABSTRACT Multiple circular and linear plasmids of Lyme disease and relapsing fever Borrelia spirochetes carry genes for members of the Bdr (Borrelia direct repeat) protein family. To define their common and divergent attributes, we first comprehensively compared the known homologs. Bdr proteins with predicted sizes ranging from 10.7 to 30.6 kDa formed five homology groups, based on variable numbers of short direct repeats in a central domain and diverse N- and C-terminal domains. In a further characterization, Western blots were probed with rabbit antisera raised against either of two purified recombinant Bdr proteins from Borrelia burgdorferi B31. The results showed that antibodies cross-react and several Bdr paralogs 19.5 to 30.5 kDa in size are expressed by cultured strain B31 in a temperature-independent manner. In situ proteolysis, immunofluorescence, and growth inhibition assays indicated that Bdr proteins are not surface exposed. Distinct patterns of cross-reacting proteins of 17.5 to 33 kDa were also detected in other B. burgdorferi, Borrelia garinii, and Borrelia afzelii strains as well as in relapsing fever spirochetesBorrelia hermsii and Borrelia turicatae. Last, we examined whether these proteins are antibody targets during Lyme disease. Analysis of 47 Lyme disease patient sera by immunoblotting and enzyme-linked immunosorbent assays showed that 24 (51%) and 20 (43%), respectively, had detectable antibodies to one or more of the Bdr proteins. Together, these data indicate that Bdr proteins constitute a family of cross-reactive Borrelia proteins which are expressed in the course of Lyme disease and in vitro.

scholarly journals Glycerol-3-Phosphate Acquisition in Spirochetes: Distribution and Biological Activity of Glycerophosphodiester Phosphodiesterase (GlpQ) among Borrelia Species

2003 ◽  
Vol 185 (4) ◽  
pp. 1346-1356 ◽  
Author(s):  
Tom G. Schwan ◽  
James M. Battisti ◽  
Stephen F. Porcella ◽  
Sandra J. Raffel ◽  
Merry E. Schrumpf ◽  
...  
Keyword(s):  
Lyme Disease ◽  
Shuttle Vector ◽  
Dihydroxyacetone Phosphate ◽  
Relapsing Fever ◽  
Borrelia Hermsii ◽  
Glycerol Facilitator ◽  
Cell Densities ◽  
Glycerol 3 Phosphate Dehydrogenase ◽  
Hydrolysis Of ◽  
Glycerophosphodiester Phosphodiesterase

ABSTRACT Relapsing-fever spirochetes achieve high cell densities (>108/ml) in their host's blood, while Lyme disease spirochetes do not (<105/ml). This striking contrast in pathogenicity of these two groups of bacteria suggests a fundamental difference in their ability to either exploit or survive in blood. Borrelia hermsii, a tick-borne relapsing-fever spirochete, contains orthologs to glpQ and glpT, genes that encode glycerophosphodiester phosphodiesterase (GlpQ) and glycerol-3-phosphate transporter (GlpT), respectively. In other bacteria, GlpQ hydrolyzes deacylated phospholipids to glycerol-3-phosphate (G3P) while GlpT transports G3P into the cytoplasm. Enzyme assays on 17 isolates of borreliae demonstrated GlpQ activity in relapsing-fever spirochetes but not in Lyme disease spirochetes. Southern blots demonstrated glpQ and glpT in all relapsing-fever spirochetes but not in the Lyme disease group. A Lyme disease spirochete, Borrelia burgdorferi, that was transformed with a shuttle vector containing glpTQ from B. hermsii produced active enzyme, which demonstrated the association of glpQ with the hydrolysis of phospholipids. Sequence analysis of B. hermsii identified glpF, glpK, and glpA, which encode the glycerol facilitator, glycerol kinase, and glycerol-3-phosphate dehydrogenase, respectively, all of which are present in B. burgdorferi. All spirochetes examined had gpsA, which encodes the enzyme that reduces dihydroxyacetone phosphate (DHAP) to G3P. Consequently, three pathways for the acquisition of G3P exist among borreliae: (i) hydrolysis of deacylated phospholipids, (ii) reduction of DHAP, and (iii) uptake and phosphorylation of glycerol. The unique ability of relapsing-fever spirochetes to hydrolyze phospholipids may contribute to their higher cell densities in blood than those of Lyme disease spirochetes.

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