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Concept: Willy Burgdorfer

170

Comparative analysis of ospC genes from 127 Borrelia burgdorferi sensu stricto strains collected in Lyme disease endemic and non-endemic European and North American regions revealed close relatedness of geographically distinct populations. OspC alleles A, B and L were detected on both continents in vectors and hosts including humans. Six ospC alleles, A, B, L, Q, R and V, were prevalent in Europe; 4 of them were detected in samples of human origin. Ten ospC alleles, A, B, D, E3, F, G, H, H3, I3 and M, were identified in the far-western U.S.A. Four ospC alleles, B, G, H and L, were abundant in the southeastern U.S.A. Here we present the first expanded analysis of ospC alleles of B. burgdorferi strains from the southeastern U.S.A with respect to their relatedness to strains from other North American and European localities. We demonstrate that ospC genotypes commonly associated with human Lyme disease in endemic European and North American regions were detected in B. burgdorferi strains isolated from non-human biting tick Ixodes affinis and rodent hosts in southeastern U.S.A. We discovered that some ospC alleles previously known only from Europe are widely distributed in the southeastern U.S.A., a finding that confirms the hypothesis of trans-oceanic migration of Borrelia species.

Concepts: Bacteria, Lyme disease, Ixodes scapularis, North America, Borrelia burgdorferi, Borrelia, Allen Steere, Willy Burgdorfer

18

The white-footed mouse (Peromyscus leucopus) is an important reservoir host for Borrelia burgdorferi, the pathogen responsible for Lyme disease, and its distribution is expanding northward. We used an Ecological Niche Factor Analysis to identify the climatic factors associated with the distribution shift of the white-footed mouse over the last 30 years at the northern edge of its range, and modeled its current and potential future (2050) distributions using the platform BIOMOD. A mild and shorter winter is favouring the northern expansion of the white-footed mouse in Québec. With more favorable winter conditions projected by 2050, the distribution range of the white-footed mouse is expected to expand further northward by 3° latitude. We also show that today in southern Québec, the occurrence of B. burgdorferi is associated with high probability of presence of the white-footed mouse. Changes in the distribution of the white-footed mouse will likely alter the geographical range of B. burgdorferi and impact the public health in northern regions that have yet to be exposed to Lyme disease.

Concepts: Bacteria, Climate, Lyme disease, Borrelia burgdorferi, Borrelia, Allen Steere, Willy Burgdorfer, White-footed Mouse

17

Although currently recommended antibiotics for Lyme disease such as doxycycline or amoxicillin cure the majority of the patients, about 10-20% of patients treated for Lyme disease may experience lingering symptoms including fatigue, pain, or joint and muscle aches. Under experimental stress conditions such as starvation or antibiotic exposure, Borrelia burgdorferi can develop round body forms, which are a type of persister bacteria that appear resistant in vitro to customary first-line antibiotics for Lyme disease. To identify more effective drugs with activity against the round body form of B. burgdorferi, we established a round body persister model induced by exposure to amoxicillin (50 μg/ml) and then screened the Food and Drug Administration drug library consisting of 1581 drug compounds and also 22 drug combinations using the SYBR Green I/propidium iodide viability assay. We identified 23 drug candidates that have higher activity against the round bodies of B. burgdorferi than either amoxicillin or doxycycline. Eleven individual drugs scored better than metronidazole and tinidazole which have been previously described to be active against round bodies. In this amoxicillin-induced round body model, some drug candidates such as daptomycin and clofazimine also displayed enhanced activity which was similar to a previous screen against stationary phase B. burgdorferi persisters not exposure to amoxicillin. Additional candidate drugs active against round bodies identified include artemisinin, ciprofloxacin, nifuroxime, fosfomycin, chlortetracycline, sulfacetamide, sulfamethoxypyridazine and sulfathiozole. Two triple drug combinations had the highest activity against amoxicillin-induced round bodies and stationary phase B. burgdorferi persisters: artemisinin/cefoperazone/doxycycline and sulfachlorpyridazine/daptomycin/doxycycline. These findings confirm and extend previous findings that certain drug combinations have superior activity against B. burgdorferi persisters in vitro, even when pre-treated with amoxicillin. These findings may have implications for improved treatment of Lyme disease.

Concepts: Bacteria, Lyme disease, Borrelia burgdorferi, Borrelia, Allen Steere, Willy Burgdorfer

14

Out of 20 spirochete species from Borrelia burgdorferi sensu lato (s.l.) complex recognized to date some are considered to have a limited distribution, while others are worldwide dispersed. Among those are Borrelia burgdorferi sensu stricto (s.s.) and Borrelia bissettii which are distributed both in North America and in Europe. While B. burgdorferi s.s. is recognized as a cause of Lyme borreliosis worldwide, involvement of B. bissettii in human Lyme disease was not so definite yet.

Concepts: Bacteria, United States, Lyme disease, Borrelia burgdorferi, Borrelia, Spirochaetes, Allen Steere, Willy Burgdorfer

12

Lyme disease is a tick-borne, multi-systemic disease, caused by the bacterium Borrelia burgdorferi. Though antibiotics are used as a primary treatment, relapse often occurs after the discontinuation of antimicrobial agents. The reason for relapse remains unknown, however previous studies suggest the possible presence of antibiotic resistant Borrelia round bodies, persisters and attached biofilm forms. Thus, there is an urgent need to find antimicrobial agents suitable to eliminate all known forms of B. burgdorferi. In this study, natural antimicrobial agents such as Apis mellifera venom and a known component, melittin, were tested using SYBR Green I/PI, direct cell counting, biofilm assays combined with LIVE/DEAD and atomic force microscopy methods. The obtained results were compared to standalone and combinations of antibiotics such as Doxycycline, Cefoperazone, Daptomycin, which were recently found to be effective against Borrelia persisters. Our findings showed that both bee venom and melittin had significant effects on all the tested forms of B. burgdorferi. In contrast, the control antibiotics when used individually or even in combinations had limited effects on the attached biofilm form. These findings strongly suggest that whole bee venom or melittin could be effective antimicrobial agents for B. burgdorferi; however, further research is necessary to evaluate their effectiveness in vivo, as well as their safe and effective delivery method for their therapeutic use.

Concepts: Bacteria, Antibiotic resistance, Effectiveness, Lyme disease, Borrelia burgdorferi, Borrelia, Allen Steere, Willy Burgdorfer

10

Two-tier serology testing is most frequently used for the diagnosis of Lyme borreliosis (LB); however, a positive result is no proof of active disease. To establish a diagnosis of active LB, better diagnostics are needed. Tests investigating the cellular immune system are available, but studies evaluating the utility of these tests on well-defined patient populations are lacking. Therefore, we investigated the utility of an enzyme-linked immunospot (ELISpot) assay to diagnose active Lyme neuroborreliosis. Peripheral blood mononuclear cells (PBMCs) of various study groups were stimulated by using Borrelia burgdorferi strain B31 and various recombinant antigens and subsequently, the number of Borrelia-specific interferon-gamma (IFN-γ) secreting T-cells was measured.We included 33 active and 37 treated Lyme neuroborreliosis patients, 28 healthy individuals treated for an early manifestation of LB in the past and 145 untreated healthy individuals. The median number of B. burgdorferi B31-specific IFN-γ secreting T-cells/2.5x105 PBMCs did not differ between active Lyme neuroborreliosis patients, treated Lyme neuroborreliosis patients and treated healthy individuals (6.0, interquartile range (IQR): 0.5 - 14.0; 4.5, IQR: 2.0 - 18.6; 7.4, IQR: 2.3 - 14.9; respectively) (p 1.000); however, the median number of B. burgdorferi B31-specific IFN-γ secreting T-cells/2.5x105 PBMCs among untreated healthy individuals was lower (2.0, IQR: 0.5 - 3.9) (p ≤0.016).We conclude that the Borrelia ELISpot, measuring the number of B. burgdorferi B31-specific INF-γ secreting T-cells/2.5x105 PBMCs, correlates with exposure to the Borrelia bacterium, but cannot be used for the diagnosis of active Lyme neuroborreliosis.

Concepts: Immune system, Bacteria, Lyme disease, Borrelia burgdorferi, Borrelia, Allen Steere, Willy Burgdorfer, Neuroborreliosis

10

The clinical manifestations of Lyme disease, caused by Borrelia burgdorferi, vary considerably in different patients, possibly due to infection by strains with varying pathogenicity. Both rRNA intergenic spacer and ospC typing methods have proven to be useful tools for categorizing B. burgdorferi strains that vary in their tendency to disseminate in humans. Neither method, however, is suitable for inferring intraspecific relationships among strains that are important for understanding the evolution of pathogenicity and the geographic spread of disease. In this study, multilocus sequence typing (MLST) was employed to investigate the population structure of B. burgdorferi recovered from human Lyme disease patients. A total of 146 clinical isolates from patients in New York and Wisconsin were divided into 53 sequence types (STs). A goeBURST analysis, that also included previously published STs from the northeastern and upper Midwestern US and adjoining areas of Canada, identified 11 major and 3 minor clonal complexes, as well as 14 singletons. The data revealed that patients from New York and Wisconsin were infected with two distinct, but genetically and phylogenetically closely related, populations of B. burgdorferi. Importantly, the data suggest the existence of B. burgdorferi lineages with differential capabilities for dissemination in humans. Interestingly, the data also indicate that MLST is better able to predict the outcome of localized or disseminated infection than is ospC typing.

Concepts: Bacteria, Infection, Infectious diseases, Lyme disease, Borrelia burgdorferi, Borrelia, Allen Steere, Willy Burgdorfer

4

Lyme borreliosis is a multisystem disorder with diverse spectrum of clinical manifestations, caused by spirochetes of the Borrelia burgdorferi sensu lato complex. It is an infectious disease that can be successfully cured by antibiotic therapy on early stages; however, the possibility of appearance of persistent signs and symptoms of disease following antibiotic treatment is recognized today. It is known that Lyme borreliosis is mimicking multiple diseases that were never proven to have a spirochete etiology. Using complete modified Kelly-Pettenkofer medium we succeeded in cultivation of live B. burgdorferi sensu lato spirochetes from samples of humans who suffered from undefined disorders, had symptoms not typical for Lyme borreliosis, but undergone antibiotic treatment due to suspicion of having Lyme disease even though they were seronegative. We report the first recovery of live Borrelia burgdorferi sensu stricto from residents of southeastern United States and first successful cultivation of live Borrelia bissettii-like strain from resident of North America. Our results support the fact that B. bissettii is responsible for human Lyme borreliosis worldwide along with B. burgdorferi s.s. Involvement of new spirochete species in Lyme borreliosis changes the understanding and recognition of clinical manifestations of this disease.

Concepts: Bacteria, Lyme disease, Borrelia burgdorferi, Borrelia, Spirochaetes, Spirochaete, Allen Steere, Willy Burgdorfer

3

Lyme disease, caused by Borrelia burgdorferi, is the most common vector-borne disease in the United States and Europe. While the majority of Lyme disease patients can resolve their symptoms if treated promptly, 10-20% of patients suffer from prolonged symptoms called post-treatment Lyme disease syndrome (PTLDS). Although the cause for PTLDS is unclear, one possibility is the presence of bacterial persisters not effectively cleared by the current Lyme antibiotics. Recent studies identified several drug candidates including daptomycin, daunomycin, doxorubicin, and mitomycin C that had good activity against B. burgdorferi persisters. However, their relative activities against B. burgdorferi persisters have not been evaluated under the same conditions. In this study, we tested the anti-persister activities of these drugs against both 7-day and 15-day old stationary phase cultures of B. burgdorferi individually as well as in combination with Lyme antibiotics doxycycline and cefuroxime (Ceftin). Our findings demonstrate daunomycin and daptomycin were more active than mitomycin C in single drug comparison at 10 and 20 μM, as well as in drug combinations with doxycycline and cefuroxime. In addition, daunomycin was more active than doxorubicin which correlated with their ability to stain and accumulate in B. burgdorferi. The two drug combination of doxycycline and cefuroxime was unable to eradicate biofilm-like microcolonies of B. burgdorferi persisters. However, the addition of either daunomycin or daptomycin to the doxycycline + cefuroxime combination completely eradicated the biofilm-like structures and produced no visible bacterial regrowth after 7 and 21 days, while the addition of doxorubicin was unable to prevent regrowth at either 7 or 21 day subculture. Mitomycin C in combination with doxycycline and cefuroxime caused no regrowth at 7 days but visible spirochetal regrowth occurred after 21 day subculture. Furthermore, we found that cefuroxime (Ceftin), the third commonly used and most active antibiotic to treat Lyme disease, could replace cefoperazone (a drug no longer available in the US) in the daptomycin + doxycycline combination with complete eradication of the biofilm-like structures as shown by lack of any regrowth in subcultures. Our findings may have implications for improved treatment of Lyme disease.

Concepts: Bacteria, Lyme disease, Borrelia burgdorferi, Borrelia, Spirochaetes, Spirochaete, Allen Steere, Willy Burgdorfer

2

Cases of Lyme borreliosis, a vector-borne zoonosis caused by bacteria in the Borrelia burgdorferi (sensu lato) species group, have increased in recent years in Europe. Knowledge of environmental factors associated with abundance of the tick vector Ixodes ricinus and the pathogen B. burgdorferi (s.l.) is of interest to understand responses to environmental changes, predict variation in risk and to inform management interventions.

Concepts: Bacteria, Lyme disease, Borrelia burgdorferi, Borrelia, Ixodes ricinus, Allen Steere, Willy Burgdorfer, Zoonoses