scholarly journals Evaluation of Nucleoside Analogs as Antimicrobials Targeting Unique Enzymes in Borrelia burgdorferi

Pathogens ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 678 ◽  
Author(s):  
Monideep Chakraborti ◽  
Samantha Schlachter ◽  
Shekerah Primus ◽  
Julie Wagner ◽  
Brandi Sweet ◽  
...  
Keyword(s):  
Lyme Disease ◽  
Borrelia Burgdorferi ◽  
Critical Role ◽  
Nucleoside Analogs ◽  
Purine Salvage ◽  
Free Living ◽  
Tick Vector ◽  
First Line Therapy ◽  
Nutritional Needs ◽  
Free Living Conditions

The first line therapy for Lyme disease is treatment with doxycycline, amoxicillin, or cefuroxime. In endemic regions, the persistence of symptoms in many patients after completion of antibiotic treatment remains a major healthcare concern. The causative agent of Lyme disease is a spirochete, Borrelia burgdorferi, an extreme auxotroph that cannot exist under free-living conditions and depends upon the tick vector and mammalian hosts to fulfill its nutritional needs. Despite lacking all major biosynthetic pathways, B. burgdorferi uniquely possesses three homologous and functional methylthioadenosine/S-adenosylhomocysteine nucleosidases (MTANs: Bgp, MtnN, and Pfs) involved in methionine and purine salvage, underscoring the critical role these enzymes play in the life cycle of the spirochete. At least one MTAN, Bgp, is exceptional in its presence on the surface of Lyme spirochetes and its dual functionality in nutrient salvage and glycosaminoglycan binding involved in host-cell adherence. Thus, MTANs offer highly promising targets for discovery of new antimicrobials. Here we report on our studies to evaluate five nucleoside analogs for MTAN inhibitory activity, and cytotoxic or cytostatic effects on a bioluminescently engineered strain of B. burgdorferi. All five compounds were either alternate substrates and/or inhibitors of MTAN activity, and reduced B. burgdorferi growth. Two inhibitors: 5′-deoxy-5′-iodoadenosine (IADO) and 5′-deoxy-5′-ethyl-immucillin A (dEt-ImmA) showed bactericidal activity. Thus, these inhibitors exhibit high promise and form the foundation for development of novel and effective antimicrobials to treat Lyme disease.

scholarly journals Does Host Complement Kill Borrelia burgdorferi within Ticks?

2003 ◽  
Vol 71 (2) ◽  
pp. 822-829 ◽  
Author(s):  
Sivaprakash Rathinavelu ◽  
Anne Broadwater ◽  
Aravinda M. de Silva
Keyword(s):  
Lyme Disease ◽  
Borrelia Burgdorferi ◽  
Outer Surface ◽  
Protein A ◽  
Surface Protein ◽  
Block Transmission ◽  
Outer Surface Protein A ◽  
Tick Vector ◽  
Host Blood ◽  
Transmission Blocking Vaccine

ABSTRACT The Lyme disease spirochete, Borrelia burgdorferi, inhabits the gut lumen of the tick vector. At this location the spirochete is exposed to host blood when a tick feeds. We report here on studies that were done with normal and complement-deficient (C3-knockout) mice to determine if the host complement system killed spirochetes within the vector. We found that spirochete numbers within feeding nymphs were not influenced by complement, most likely because host complement was inactivated within the vector. The Lyme disease outer surface protein A (OspA) vaccine is a transmission-blocking vaccine that targets spirochetes in the vector. In experiments with mice hyperimmunized with OspA, complement was not required to kill spirochetes within nymphs and to block transmission from nymphs to the vaccinated host. However, host complement did enhance the ability of OspA antibody to block larvae from acquiring spirochetes. Thus, the effects of OspA antibody on nymphal transmission and larval acquisition appear to be based on different mechanisms.

scholarly journals The unusual cell wall of the Lyme disease spirochaete Borrelia burgdorferi is shaped by a tick sugar

2021 ◽  
Vol 6 (12) ◽  
pp. 1583-1592
Author(s):  
Tanner G. DeHart ◽  
Mara R. Kushelman ◽  
Sherry B. Hildreth ◽  
Richard F. Helm ◽  
Brandon L. Jutras
Keyword(s):  
Cell Wall ◽  
Lyme Disease ◽  
Borrelia Burgdorferi ◽  
Cell Walls ◽  
Structural Strength ◽  
Cell Envelope ◽  
Wild Type ◽  
Tick Vector ◽  
Cell Wall Alteration ◽  
Main Component

AbstractPeptidoglycan—a mesh sac of glycans that are linked by peptides—is the main component of bacterial cell walls. Peptidoglycan provides structural strength, protects cells from osmotic pressure and contributes to shape. All bacterial glycans are repeating disaccharides of N-acetylglucosamine (GlcNAc) β-(1–4)-linked to N-acetylmuramic acid (MurNAc). Borrelia burgdorferi, the tick-borne Lyme disease pathogen, produces glycan chains in which MurNAc is occasionally replaced with an unknown sugar. Nuclear magnetic resonance, liquid chromatography–mass spectroscopy and genetic analyses show that B. burgdorferi produces glycans that contain GlcNAc–GlcNAc. This unusual disaccharide is chitobiose, a component of its chitinous tick vector. Mutant bacteria that are auxotrophic for chitobiose have altered morphology, reduced motility and cell envelope defects that probably result from producing peptidoglycan that is stiffer than that in wild-type bacteria. We propose that the peptidoglycan of B. burgdorferi probably evolved by adaptation to obligate parasitization of a tick vector, resulting in a biophysical cell-wall alteration to withstand the atypical torque associated with twisting motility.

scholarly journals Chemotaxis in Borrelia burgdorferi

1998 ◽  
Vol 180 (2) ◽  
pp. 231-235 ◽  
Author(s):  
Wenyuan Shi ◽  
Zhaomin Yang ◽  
Yongzhi Geng ◽  
Lawrence E. Wolinsky ◽  
Michael A. Lovett
Keyword(s):  
Amino Acids ◽  
Lyme Disease ◽  
Borrelia Burgdorferi ◽  
Interstitial Fluid ◽  
Chemical Compounds ◽  
Rabbit Serum ◽  
Free Living ◽  
Physiological Functions ◽  
Causative Microorganism

ABSTRACT Borrelia burgdorferi is a motile spirochete which has been identified as the causative microorganism in Lyme disease. The physiological functions which govern the motility of this organism have not been elucidated. In this study, we found that motility of B. burgdorferi required an environment similar to interstitial fluid (e.g., pH 7.6 and 0.15 M NaCl). Several methods were used to detect and measure chemotaxis of B. burgdorferi. A number of chemical compounds and mixtures were surveyed for the ability to induce positive and negative chemotaxis of B. burgdorferi. Rabbit serum was found to be an attractant for B. burgdorferi, while ethanol and butanol were found to be repellents. Unlike some free-living spirochetes (e.g., Spirochaeta aurantia), B. burgdorferi did not exhibit any observable chemotaxis to common sugars or amino acids. A method was developed to produce spirochete cells with a self-entangled end. These cells enabled us to study the rotation of a single flagellar bundle in response to chemoattractants or repellents. The study shows that the frequency and duration for pausing of flagella are important for chemotaxis of B. burgdorferi.

scholarly journals Prevalence of IgG Antibodies against Borrelia Burgdorferi S.L. and Ehrlichia Phagocytophila in Sera of Patients Presenting Symptoms of Lyme Disease in a Central Region of Italy

2002 ◽  
Vol 15 (3) ◽  
pp. 245-248 ◽  
Author(s):  
I. Santino ◽  
R. Grillo ◽  
M. Nicoletti ◽  
D. Santapaola ◽  
D. Speziale ◽  
...  
Keyword(s):  
Lyme Disease ◽  
Borrelia Burgdorferi ◽  
Central Italy ◽  
Clinical Manifestations ◽  
Microbial Pathogens ◽  
Tick Vector ◽  
Ehrlichia Phagocytophila ◽  
Presenting Symptoms ◽  
Borrelia Burgdorferi S.L ◽  
Index Value

The aim of this study was to evaluate the prevalence (seroprevalence) of antibodies against Borrelia burgdorferi and Ehrlichia phagocytophila among patients resident in Lazio, a region of central Italy. Of a sample of 1,050 patients, which presented clinical manifestations related to Lyme disease, 34 (3.2%) were Borrelia-seropositive (Lyme index value ≥ 1.2). The sera of 25 out of the 34 patients that were Borrelia-positive were also analysed for the presence of antibodies against E. phagocytophila and 3 (12%) were found Ehrlichia-positive (titres >1:64). No Ehrlichia-positive samples were found among sera of 250 Borrelia-negative patients. Since both B. burgdorferi s.l. and Ehrlichia species share the same tick vector ( Ixodes ricinus), our results indicate that concurrent transmission of these microbial pathogens might have been occurred among the patients included in this study.

The effect of infection with Lyme disease spirochetes (Borrelia burgdorferi) on the phototaxis, activity, and questing height of the tick vector Ixodes scapularis

Parasitology ◽  
1996 ◽  
Vol 113 (2) ◽  
pp. 97-103 ◽  
Author(s):  
H. Lefcort ◽  
L. A. Durden
Keyword(s):  
Lyme Disease ◽  
Borrelia Burgdorferi ◽  
Kin Selection ◽  
Ixodes Scapularis ◽  
Bacterial Pathogen ◽  
Pathogen Transmission ◽  
Ecological Effects ◽  
Infected Tick ◽  
Tick Vector ◽  
Tick Vectors

SUMMARYLittle is known about the effects of infection with Borrelia burgdorferi, the bacterium that causes Lyme disease, on its tick vectors. The purpose of this study was to determine the behavioural and ecological effects of infection by the bacterium in nymphal and adult black-legged (Ixodes scapularis) ticks. We found that the effects of infection were more pronounced in adults than in nymphs. Compared to uninfected adults, infected adults were less able to overcome physical obstacles, avoided vertical surfaces, were less active and quested at lower heights. Infected nymphs showed increased phototaxis and attraction to vertical surfaces. Infected nymphs also showed trends toward increased questing height and a greater tendency to overcome physical obstacles although these trends were not statistically significant. These altered behaviours in an infected tick may affect survival or pathogen transmission and may reflect kin selection in the bacterial pathogen.

scholarly journals An lp17-encoded small non-coding RNA with a potential regulatory role in mammalian host adaptation by the Lyme disease spirochete

2020 ◽  
Author(s):  
Michael A. Crowley ◽  
Troy Bankhead
Keyword(s):  
Lyme Disease ◽  
Borrelia Burgdorferi ◽  
Intergenic Region ◽  
Critical Role ◽  
Protein Translation ◽  
The United States ◽  
Host Adaptation ◽  
Mammalian Host ◽  
Intergenic Sequence ◽  
Bacterial Gene

AbstractThe bacterial agent of Lyme disease, Borrelia burgdorferi, relies on an intricate gene regulatory network to transit between the disparate Ixodes tick vector and mammalian host environments. We recently reported that a B. burgdorferi mutant lacking an intergenic region of lp17 displayed attenuated murine tissue colonization and pathogenesis due to altered antigen expression. In this study, a more detailed characterization of the putative regulatory factor encoded by the region was pursued through genetic complementation of the mutant with variants of the intergenic sequence. In cis complemented strains featuring mutations aimed at eliminating potential BBD07 protein translation were capable of full tissue colonization, suggesting that the region encodes an sRNA. In trans complementation resulted in elevated transcription levels and was found to completely abolish infectivity in both immunocompetent and immunodeficient mice. Quantitative analysis of transcription of the putative sRNA by wild type B. burgdorferi showed it to be highly induced during murine infection. Lastly, targeted deletion of this region resulted in significant changes to the transcriptome, including genes with potential roles in transmission and host adaptation. The findings reported herein strongly suggest that this lp17 intergenic region encodes for an sRNA with a critical role in the gene regulation required for adaptation and persistence of the pathogen in the mammalian host.Author SummaryLyme disease continues to emerge as a devastating infection that afflicts hundreds of thousands of people annually in the United States and abroad, highlighting the need for new approaches and targets for intervention. Successful development of these therapies relies heavily on an improved understanding of the biology of the causative agent, Borrelia burgdorferi. This is particularly true for the critical points in the life cycle of the pathogen where it must transition between ticks and mammals. Variation in the levels of bacterial gene expression is the lynchpin of this transition and is known to be driven partly by the activity of regulatory molecules known as small non-coding RNAs (sRNAs). In this work, we characterize one of these sRNAs by providing experimental evidence that the transcribed product does not code for a protein, by testing the effects of its overproduction on infectivity, and by interrogating whether its activity causes changes in expression levels of genes at the level of transcription. The findings of this study provide further evidence that regulatory sRNA activity is critical for transmission and optimal infectivity of B. burgdorferi and contribute to the recently growing effort to attribute specific roles to these important molecules in the context of Lyme disease.

scholarly journals Regulatory Protein BBD18 of the Lyme Disease Spirochete: Essential Role During Tick Acquisition?

mBio ◽  
2014 ◽  
Vol 5 (2) ◽  
Author(s):  
Beth M. Hayes ◽  
Daniel P. Dulebohn ◽  
Amit Sarkar ◽  
Kit Tilly ◽  
Aaron Bestor ◽  
...  
Keyword(s):  
Lyme Disease ◽  
Borrelia Burgdorferi ◽  
Critical Role ◽  
Regulatory Protein ◽  
Site Directed Mutagenesis ◽  
Mammalian Host ◽  
Content Type ◽  
Block Transmission ◽  
Infectious Cycle

ABSTRACTThe Lyme disease spirocheteBorrelia burgdorferisenses and responds to environmental cues as it transits between the tick vector and vertebrate host. Failure to properly adapt can block transmission of the spirochete and persistence in either vector or host. We previously identified BBD18, a novel plasmid-encoded protein ofB. burgdorferi, as a putative repressor of the host-essential factor OspC. In this study, we investigate thein vivorole of BBD18 as a regulatory protein, using an experimental mouse-tick model system that closely resembles the natural infectious cycle ofB. burgdorferi. We show that spirochetes that have been engineered to constitutively produce BBD18 can colonize and persist in ticks but do not infect mice when introduced by either tick bite or needle inoculation. Conversely, spirochetes lacking BBD18 can persistently infect mice but are not acquired by feeding ticks. Through site-directed mutagenesis, we have demonstrated that abrogation of spirochete infection in mice by overexpression of BBD18 occurs only withbbd18alleles that can suppress OspC synthesis. Finally, we demonstrate that BBD18-mediated regulation does not utilize a previously describedospCoperator sequence required byB. burgdorferifor persistence in immunocompetent mice. These data lead us to conclude that BBD18 does not represent the putative repressor utilized byB. burgdorferifor the specific downregulation of OspC in the mammalian host. Rather, we suggest that BBD18 exhibits features more consistent with those of a global regulatory protein whose critical role occurs during spirochete acquisition by feeding ticks.IMPORTANCELyme disease, caused byBorrelia burgdorferi, is the most common arthropod-borne disease in North America.B. burgdorferiis transmitted to humans and other vertebrate hosts by ticks as they take a blood meal. Transmission between vectors and hosts requires the bacterium to sense changes in the environment and adapt. However, the mechanisms involved in this process are not well understood. By determining howB. burgdorfericycles between two very different environments, we can potentially establish novel ways to interfere with transmission and limit infection of this vector-borne pathogen. We are studying a regulatory protein called BBD18 that we recently described. We found that too much BBD18 interferes with the spirochete’s ability to establish infection in mice, whereas too little BBD18 appears to prevent colonization in ticks. Our study provides new insight into key elements of the infectious cycle of the Lyme disease spirochete.

scholarly journals Borrelia burgdorferi Harbors a Transport System Essential for Purine Salvage and Mammalian Infection

2012 ◽  
Vol 80 (9) ◽  
pp. 3086-3093 ◽  
Author(s):  
Sunny Jain ◽  
Selina Sutchu ◽  
Patricia A. Rosa ◽  
Rebecca Byram ◽  
Mollie W. Jewett
Keyword(s):  
Lyme Disease ◽  
Borrelia Burgdorferi ◽  
Transport System ◽  
De Novo ◽  
Transport Systems ◽  
Mammalian Host ◽  
Salvage Pathway ◽  
Purine Salvage ◽  
Content Type ◽  
Obligate Pathogen

ABSTRACTBorrelia burgdorferiis the tick-borne bacterium that causes the multistage inflammatory disease Lyme disease.B. burgdorferihas a reduced genome and lacks the enzymes required forde novosynthesis 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 forB. burgdorferisurvival 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 byB. burgdorferihave yet to be identified. Herein, we demonstrate that the genesbbb22andbbb23, present onB. 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. burgdorferilackingbbb22-23was noninfectious in mice up to a dose of 1 × 107spirochetes. Together, our data establish thatbbb22-23encode purine permeases critical forB. burgdorferimammalian infectivity, suggesting that this transport system may serve as a novel antimicrobial target for the treatment of Lyme disease.

Geographic Uniformity of the Lyme Disease Spirochete (Borrelia burgdorferi) and Its Shared History With Tick Vector (Ixodes scapularis) in the Northeastern United States

Genetics ◽  
2002 ◽  
Vol 160 (3) ◽  
pp. 833-849
Author(s):  
Wei-Gang Qiu ◽  
Daniel E Dykhuizen ◽  
Michael S Acosta ◽  
Benjamin J Luft
Keyword(s):  
United States ◽  
Genetic Structure ◽  
Lyme Disease ◽  
Borrelia Burgdorferi ◽  
Ixodes Scapularis ◽  
Balancing Selection ◽  
Natural Populations ◽  
The United States ◽  
High Genetic Diversity ◽  
Tick Vector

Abstract Over 80% of reported cases of Lyme disease in the United States occur in coastal regions of northeastern and mid-Atlantic states. The genetic structure of the Lyme disease spirochete (Borrelia burgdorferi) and its main tick vector (Ixodes scapularis) was studied concurrently and comparatively by sampling natural populations of I. scapularis ticks along the East Coast from 1996 to 1998. Borrelia is genetically highly diverse at the outer surface protein ospC. Since Borrelia is highly clonal, the ospC alleles can be used to define clones. A newly designed reverse line blotting (RLB) assay shows that up to 10 Borrelia clones can infect a single tick. The clone frequencies in Borrelia populations are the same across the Northeast. On the other hand, I. scapularis populations show strong regional divergence (among northeastern, mid-Atlantic, and southern states) as well as local differentiation. The high genetic diversity within Borrelia populations and the disparity in the genetic structure between Borrelia and its tick vector are likely consequences of strong balancing selection on local Borrelia clones. Demographically, both Borrelia and I. scapularis populations in the Northeast show the characteristics of a species that has recently expanded from a population bottleneck. Major geological and ecological events, such as the last glacial maximum (18,000 years ago) and the modern-day expansion of tick habitats, are likely causes of the observed “founder effects” for the two organisms in the Northeast. We therefore conclude that the genetic structure of B. burgdorferi has been intimately shaped by the natural history of its main vector, the northern lineage of I. scapularis ticks.

scholarly journals bptA (bbe16) is essential for the persistence of the Lyme disease spirochete, Borrelia burgdorferi, in its natural tick vector

2005 ◽  
Vol 102 (19) ◽  
pp. 6972-6977 ◽  
Author(s):  
A. T. Revel ◽  
J. S. Blevins ◽  
C. Almazan ◽  
L. Neil ◽  
K. M. Kocan ◽  
...  
Keyword(s):  
Lyme Disease ◽  
Borrelia Burgdorferi ◽  
Tick Vector
Sign in / Sign up

Export Citation Format

Share Document