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The number of Lyme disease cases (Lyme borreliosis) in Ontario, Canada has increased over the last decade, and that figure is projected to continue to increase. The northern limit of Lyme disease cases has also been progressing northward from the northeastern United States into southeastern Ontario. Several factors such as climate change, changes in host abundance, host and vector migration, or possibly a combination of these factors likely contribute to the emergence of Lyme disease cases in eastern Ontario. This study first determined areas of warming using time series remotely sensed temperature data within Ontario, then analyzed possible spatial-temporal changes in Lyme disease risk in eastern Ontario from 2000 to 2013 due to climate change using tick population modeling. The outputs of the model were validated by using tick surveillance data from 2002 to 2012. Our results indicated areas in Ontario where Lyme disease risk changed from unsustainable to sustainable for sustaining Ixodes scapularis (black-legged tick) populations. This study provides evidence that climate change has facilitated the northward expansion of black-legged tick populations’ geographic range over the past decade. The results demonstrate that remote sensing data can be used to increase the spatial detail for Lyme disease risk mapping and provide risk maps for better awareness of possible Lyme disease cases. Further studies are required to determine the contribution of host migration and abundance on changes in eastern Ontario’s Lyme disease risk. Full article

Improvements to risk assessments are needed to enhance our understanding of tick-borne disease epidemiology. We review tick vectors and duration of tick attachment required for pathogen transmission for the following pathogens/toxins and diseases: (1) Anaplasma phagocytophilum (anaplasmosis); (2) Babesia microti (babesiosis); (3) Borrelia burgdorferi (Lyme disease); (4) Southern tick-associated rash illness; (5) Borrelia hermsii (tick-borne relapsing fever); (6) Borrelia parkeri (tick-borne relapsing fever); (7) Borrelia turicatae (tick-borne relapsing fever); (8) Borrelia mayonii; (9) Borrelia miyamotoi; (10) Coxiella burnetii (Query fever); (11) Ehrlichia chaffeensis (ehrlichiosis); (12) Ehrlichia ewingii (ehrlichiosis); (13) Ehrlichia muris; (14) Francisella tularensis (tularemia); (15) Rickettsia 364D; (16) Rickettsia montanensis; (17) Rickettsia parkeri (American boutonneuse fever, American tick bite fever); (18) Rickettsia ricketsii (Rocky Mountain spotted fever); (19) Colorado tick fever virus (Colorado tick fever); (20) Heartland virus; (21) Powassan virus (Powassan disease); (22) tick paralysis neurotoxin; and (23) Galactose-α-1,3-galactose (Mammalian Meat Allergy-alpha-gal syndrome). Published studies for 12 of the 23 pathogens/diseases showed tick attachment times. Reported tick attachment times varied (<1 h to seven days) between pathogen/toxin type and tick vector. Not all studies were designed to detect the duration of attachment required for transmission. Knowledge of this important aspect of vector competence is lacking and impairs risk assessment for some tick-borne pathogens. Full article

Lyme disease is a most common vector-borne disease in the US. Although the majority of Lyme patients can be cured with the standard two- to four-week antibiotic treatment, at least 10%–20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, one possibility is that persisting organisms are not killed by current Lyme antibiotics. In our previous studies, we screened an FDA drug library and an NCI compound library on B. burgdorferi and found some drug hits including sulfa drugs as having good activity against B. burgdorferi stationary phase cells. In this study, we evaluated the relative activity of three commonly used sulfa drugs, sulfamethoxazole (Smx), dapsone (Dps), sulfachlorpyridazine (Scp), and also trimethoprim (Tmp), and assessed their combinations with the commonly prescribed Lyme antibiotics for activities against B. burgdorferi stationary phase cells. Using the same molarity concentration, dapsone, sulfachlorpyridazine and trimethoprim showed very similar activity against stationary phase B. burgdorferi enriched in persisters; however, sulfamethoxazole was the least active drug among the three sulfa drugs tested. Interestingly, contrary to other bacterial systems, Tmp did not show synergy in drug combinations with the three sulfa drugs at their clinically relevant serum concentrations against B. burgdorferi. We found that sulfa drugs combined with other antibiotics were more active than their respective single drugs and that four-drug combinations were more active than three-drug combinations. Four-drug combinations dapsone + minocycline + cefuroxime + azithromycin and dapsone + minocycline + cefuroxime + rifampin showed the best activity against stationary phase B. burgdorferi in these sulfa drug combinations. However, these four-sulfa-drug–containing combinations still had considerably less activity against B. burgdorferi stationary phase cells than the Daptomycin + cefuroxime + doxycycline used as a positive control which completely eradicated B. burgdorferi stationary phase cells. Future studies are needed to evaluate and optimize the sulfa drug combinations in vitro and also in animal models. Full article

Anaplasma phagocytophilum and Borrelia burgdorferi are two tick-borne bacteria that cause disease in people and animals. For each of these bacteria, there is a complex of closely related genospecies and/or strains that are genetically distinct and have been shown through both observational and experimental studies to have different host tropisms. In this review we compare the known ecologies of these two bacterial complexes in the far western USA and find remarkable similarities, which will help us understand evolutionary histories and coadaptation among vertebrate host, tick vector, and bacteria. For both complexes, sensu stricto genospecies (those that infect humans) share a similar geographic range, are vectored mainly by ticks in the Ixodes ricinus-complex, utilize mainly white-footed mice (Peromyscus leucopus) as a reservoir in the eastern USA and tree squirrels in the far west, and tend to be generalists, infecting a wider variety of vertebrate host species. Other sensu lato genospecies within each complex are generally more specialized, occurring often in local enzootic cycles within a narrow range of vertebrate hosts and specialized vector species. We suggest that these similar ecologies may have arisen through utilization of a generalist tick species as a vector, resulting in a potentially more virulent generalist pathogen that spills over into humans, vs. utilization of a specialized tick vector on a particular vertebrate host species, promoting microbe specialization. Such tight host-vector-pathogen coupling could also facilitate high enzootic prevalence and the evolution of host immune-tolerance and bacterial avirulence. Full article

A novel isothermal detection for recombinase polymerase amplification with lateral flow (LF-RPA) was established for Borrelia burgdorferi (B. burgdorferi) detection in this study. This assay with high sensitivity and specificity can get a visible result without any additional equipment in 30 min. We designed a pair of primers according to recA gene of B. burgdorferi strains and a methodology evaluation was performed. The results showed that the RPA assay based on the recA gene was successfully applied in B. burgdorferi detection, and its specific amplification was only achieved from the genomic DNA of B. burgdorferi. The detection limit of the new assay was about 25 copies of the B. burgdorferi genomic DNA. Twenty Lyme borreliosis patients’ serum samples were detected by LF-RPA assay, real-time qPCR and nested-PCR. Results showed the LF-RPA assay is more effective than nested-PCR for its shorter reaction time and considerably higher detection rate. This method is of great value in clinical rapid detection for Lyme borreliosis. Using the RPA assay might be a megatrend for DNA detection in clinics and endemic regions. Full article

Evading innate immunity is a prerequisite for pathogenic microorganisms in order to survive in their respective hosts. Concerning Lyme disease spirochetes belonging to the Borrelia (B.) burgdorferi sensu lato group, a broad range of diverse vertebrates serve as reservoir or even as incidental hosts, including humans. The capability to infect multiple hosts implies that spirochetes have developed sophisticated means to counter the destructive effects of complement of humans and various animals. While the means by which spirochetes overcome the hosts immune defense are far from being completely understood, there is a growing body of evidence suggesting that binding of the key regulator of the alternative pathway, Factor H, plays a pivotal role for immune evasion and that Factor H is an important determinant of host specificity. This review covers (i) the contribution of complement in host-specificity and transmissibility of Lyme disease spirochetes; (ii) the involvement of borrelial-derived determinants to host specificity; (iii) the interplay of human and animal Factor H with complement-acquiring surface proteins of diverse borrelial species; and (iv) the potential role of additional animal complement proteins in the immune evasion of spirochetes. Full article

Borrelia burgdorferi, the spirochetal agent of Lyme disease, is maintained in nature in a cycle involving a tick vector and a mammalian host. Adaptation to the diverse conditions of temperature, pH, oxygen tension and nutrient availability in these two environments requires the precise orchestration of gene expression. Over 25 microarray analyses relating to B. burgdorferi genomics and transcriptomics have been published. The majority of these studies has explored the global transcriptome under a variety of conditions and has contributed substantially to the current understanding of B. burgdorferi transcriptional regulation. In this review, we present a summary of these studies with particular focus on those that helped define the roles of transcriptional regulators in modulating gene expression in the tick and mammalian milieus. By performing comparative analysis of results derived from the published microarray expression profiling studies, we identified composite gene lists comprising differentially expressed genes in these two environments. Further, we explored the overlap between the regulatory circuits that function during the tick and mammalian phases of the enzootic cycle. Taken together, the data indicate that there is interplay among the distinct signaling pathways that function in feeding ticks and during adaptation to growth in the mammal. Full article

Given the relatively recent recognition of Lyme disease (LD) by CDC in 1990 as a nationally notifiable infectious condition, the rise of reported human cases every year argues for a better understanding of its geographic scope. The aim of this inquiry was to explore research conducted on spatiotemporal patterns of Lyme disease in order to identify strategies for implementing vector and reservoir-targeted interventions. The focus of this review is on the use of GIS-based methods to study populations of the reservoir hosts, vectors and humans in addition to the spatiotemporal interactions between these populations. New GIS-based studies are monitoring occurrence at the macro-level, and helping pinpoint areas of occurrence at the micro-level, where spread within populations of reservoir hosts, clusters of infected ticks and tick to human transmission may be better understood. Full article

Lyme disease is a leading vector-borne disease in the United States. Although the majority of Lyme patients can be cured with standard 2–4 week antibiotic treatment, 10%–20% of patients continue to suffer from prolonged post-treatment Lyme disease syndrome (PTLDS). While the cause for this is unclear, persisting organisms not killed by current Lyme antibiotics may be involved. In our previous study, we screened an FDA drug library and reported 27 top hits that showed high activity against Borrelia persisters. In this study, we present the results of an additional 113 active hits that have higher activity against the stationary phase B. burgdorferi than the currently used Lyme antibiotics. Many antimicrobial agents (antibiotics, antivirals, antifungals, anthelmintics or antiparasitics) used for treating other infections were found to have better activity than the current Lyme antibiotics. These include antibacterials such as rifamycins (3-formal-rifamycin, rifaximin, rifamycin SV), thiostrepton, quinolone drugs (sarafloxacin, clinafloxacin, tosufloxacin), and cell wall inhibitors carbenicillin, tazobactam, aztreonam; antifungal agents such as fluconazole, mepartricin, bifonazole, climbazole, oxiconazole, nystatin; antiviral agents zanamivir, nevirapine, tilorone; antimalarial agents artemisinin, methylene blue, and quidaldine blue; antihelmintic and antiparasitic agents toltrazuril, tartar emetic, potassium antimonyl tartrate trihydrate, oxantel, closantel, hycanthone, pyrimethamine, and tetramisole. Interestingly, drugs used for treating other non-infectious conditions including verteporfin, oltipraz, pyroglutamic acid, pidolic acid, and dextrorphan tartrate, that act on the glutathione/γ-glutamyl pathway involved in protection against free radical damage, and also the antidepressant drug indatraline, were found to have high activity against stationary phase B. burgdorferi. Among the active hits, agents that affect cell membranes, energy production, and reactive oxygen species production are more active against the B. burgdorferi persisters than the commonly used antibiotics that inhibit macromolecule biosynthesis. Future studies are needed to evaluate and optimize the promising active hits in drug combination studies in vitro and also in vivo in animal models. These studies may have implications for developing more effective treatments of Lyme disease. Full article

Epidemiological data often include excess zeros. This is particularly the case for data on rare conditions, diseases that are not common in specific areas or specific time periods, and conditions and diseases that are hard to detect or on the rise. In this paper, we provide a review of methods for modeling data with excess zeros with focus on count data, namely hurdle and zero-inflated models, and discuss extensions of these models to data with spatial and spatio-temporal dependence structures. We consider a Bayesian hierarchical framework to implement spatial and spatio-temporal models for data with excess zeros. We further review current implementation methods and computational tools. Finally, we provide a case study on five-year counts of confirmed cases of Lyme disease in Illinois at the county level. Full article

Lyme borreliosis, caused by the bacterium, Borrelia burgdorferi, is an emerging vector-borne infectious disease in Canada. According to the Public Health Agency of Canada (PHAC), by the year 2020, 80% of Canadians will live in Lyme endemic areas. An understanding of the association of Ixodes scapularis, the main vector of Lyme disease, with it hosts is a fundamental component in assessing changes in the spatial distribution of human risk for Lyme disease. Through the application of Geographic Information System (GIS) mapping methods and spatial analysis techniques, this study examines the population dynamics of the black-legged Lyme tick and its primary host, the white-tailed deer, in eastern Ontario, Canada. By developing a habitat suitability model through a GIS-based multi-criteria decision making (MCDM) analysis, the relationship of the deer habitat suitability map was generated and the results were compared with deer harvest data. Tick submission data collected from two public health units between 2006 and 2012 were used to explore the relationship between endemic ticks and deer habitat suitability in eastern Ontario. The positive correlation demonstrated between the deer habitat suitability model and deer harvest data allows us to further analyze the association between deer habitat and black-legged ticks in our study area. Our results revealed that the high tick submission number corresponds with the high suitability. These results are useful for developing management strategies that aim to prevent Lyme from becoming a threat to public health in Canada. Further studies are required to investigate how tick survival, behaviour and seasonal activity may change with projected climate change. Full article

A highly conserved 357-bp segment of the 16S ribosomal RNA gene (16S rDNA) of Borrelia burgdorferi sensu lato and the correspondent 358-bp segment of the Borrelia miyamotoi gene were amplified by a single pair of nested polymerase chain reaction (PCR) primers for detection, and the amplicons were used as the templates for direct Sanger DNA sequencing. Reliable molecular diagnosis of these borreliae was confirmed by sequence alignment analysis of the hypervariable regions of the PCR amplicon, using the Basic Local Alignment Search Tool (BLAST) provided by the GenBank. This methodology can detect and confirm B. burgdorferi and B. miyamotoi in blood samples of patients with off-season spirochetemia of low bacterial density. We found four B. miyamotoi infections among 14 patients with spirochetemia, including one patient co-infected by both B. miyamotoi and B. burgdorferi in a winter month when human exposure to tick bites is very limited in the Northeast of the U.S.A. We conclude that sensitive and reliable tests for these two Borrelia species should be implemented in the microbiology laboratory of hospitals located in the disease-endemic areas, for timely diagnosis and appropriate treatment of the patients at an early stage of the infection to prevent potential tissue damages. Full article

The diagnoses of Lyme disease based on clinical manifestations, serological findings and detection of infectious agents often contradict each other. We tested 52 blind-coded serum samples, including 20 pre-treatment and 12 post-treatment sera from clinically suspect Lyme disease patients, for the presence of residual Lyme disease infectious agents, using nested PCR amplification of a signature segment of the borrelial 16S ribosomal RNA gene for detection and direct DNA sequencing of the PCR amplicon for molecular validation. These archived sera were split from the samples drawn for the 2-tier serology tests performed by a CDC-approved laboratory, and are used as reference materials for evaluating new diagnostic reagents. Of the 12 post-treatment serum samples, we found DNA evidence of a novel borrelia of uncertain significance in one, which was also positive for the 2-tier serology test. The rest of the post-treatment sera and all 20 control sera were PCR-negative. Of the 20 pre-treatment sera from clinically suspect early Lyme disease patients, we found Borrelia miyamotoi in one which was 2-tier serology-negative, and a Borrelia burgdorferi in two—one negative and one positive for 2-tier serology. We conclude that a sensitive and reliable DNA-based test is needed to support the diagnosis of Lyme disease and Lyme disease-like borreliosis. Full article

This paper reports a 17-year seroepidemiological surveillance study of Borrelia burgdorferi infection, performed with the aim of improving our knowledge of the epidemiology of this pathogen. Serum samples (1,179) from patients (623, stratified with respect to age, sex, season, area of residence and occupation) bitten by ticks in two regions of northern Spain were IFA-tested for B. burgdorferi antibodies. Positive results were confirmed by western blotting. Antibodies specific for B. burgdorferi were found in 13.3% of the patients; 7.8% were IgM positive, 9.6% were IgG positive, and 4.33% were both IgM and IgG positive. Five species of ticks were identified in the seropositive patients: Dermacentor marginatus (41.17% of such patients) Dermacentor reticulatus (11.76%), Rhiphicephalus sanguineus (17.64%), Rhiphicephalus turanicus (5.88%) and Ixodes ricinus (23.52%). B. burgdorferi DNA was sought by PCR in ticks when available. One tick, a D. reticulatus male, was found carrying the pathogen. The seroprevalence found was similar to the previously demonstrated in similar studies in Spain and other European countries. Full article

Lyme Borreliosis is an infectious disease caused by the spirochete Borrelia burgdorferi that is transmitted through the bite of infected ticks. Both B cell-mediated humoral immunity and T cell immunity develop during natural Borrelia infection. However, compared with humoral immunity, the T cell response to Borrelia infection has not been well elucidated. In this study, a novel T cell-based assay was developed and validated for the sensitive detection of antigen-specific T cell response to B. burgdorferi. Using interferon-g as a biomarker, we developed a new enzyme-linked immunospot method (iSpot Lyme™) to detect Borrelia antigen-specific effector/memory T cells that were activated in vivo by exposing them to recombinant Borrelia antigens ex vivo. To test this new method as a potential laboratory diagnostic tool, we performed a clinical study with a cohort of Borrelia positive patients and healthy controls. We demonstrated that the iSpot Lyme assay has a significantly higher specificity and sensitivity compared with the Western Blot assay that is currently used as a diagnostic measure. A comprehensive evaluation of the T cell response to Borrelia infection should, therefore, provide new insights into the pathogenesis, diagnosis, treatment and monitoring of Lyme disease. Full article

Poikilothermic disease vectors can respond to altered climates through spatial changes in both population size and phenology. Quantitative descriptors to characterize, analyze and visualize these dynamic responses are lacking, particularly across large spatial domains. In order to demonstrate the value of a spatially explicit, dynamic modeling approach, we assessed spatial changes in the population dynamics of Ixodes scapularis, the Lyme disease vector, using a temperature-forced population model simulated across a grid of 4 × 4 km cells covering the eastern United States, using both modeled (Weather Research and Forecasting (WRF) 3.2.1) baseline/current (2001–2004) and projected (Representative Concentration Pathway (RCP) 4.5 and RCP 8.5; 2057–2059) climate data. Ten dynamic population features (DPFs) were derived from simulated populations and analyzed spatially to characterize the regional population response to current and future climate across the domain. Each DPF under the current climate was assessed for its ability to discriminate observed Lyme disease risk and known vector presence/absence, using data from the US Centers for Disease Control and Prevention. Peak vector population and month of peak vector population were the DPFs that performed best as predictors of current Lyme disease risk. When examined under baseline and projected climate scenarios, the spatial and temporal distributions of DPFs shift and the seasonal cycle of key questing life stages is compressed under some scenarios. Our results demonstrate the utility of spatial characterization, analysis and visualization of dynamic population responses—including altered phenology—of disease vectors to altered climate. Full article

The gravity models are commonly used spatial interaction models. They have been widely applied in a large set of domains dealing with interactions amongst spatial entities. The spread of vector-borne diseases is also related to the intensity of interaction between spatial entities, namely, the physical habitat of pathogens’ vectors and/or hosts, and urban areas, thus humans. This study implements the concept behind gravity models in the spatial spread of two vector-borne diseases, nephropathia epidemica and Lyme borreliosis, based on current knowledge on the transmission mechanism of these diseases. Two sources of information on vegetated systems were tested: the CORINE land cover map and MODIS NDVI. The size of vegetated areas near urban centers and a local indicator of occupation-related exposure were found significant predictors of disease risk. Both the land cover map and the space-borne dataset were suited yet not equivalent input sources to locate and measure vegetated areas of importance for disease spread. The overall results point at the compatibility of the gravity model concept and the spatial spread of vector-borne diseases. Full article