Tick-human interactions: from allergic klendusity to the α-Gal syndrome.

Ticks and the pathogens they transmit, including bacteria, viruses, protozoa, and helminths, constitute a growing burden for human and animal health worldwide. The ability of some animal species to acquire resistance to blood-feeding by ticks after a single or repeated infestation is known as acquired tick resistance (ATR). This resistance has been associated to tick-specific IgE response, the generation of skin-resident memory CD4+ T cells, basophil recruitment, histamine release, and epidermal hyperplasia. ATR has also been associated with protection to tick-borne tularemia through allergic klendusity, a disease-escaping ability produced by the development of hypersensitivity to an allergen. In addition to pathogen transmission, tick infestation in humans is associated with the α-Gal syndrome (AGS), a type of allergy characterized by an IgE response against the carbohydrate Galα1-3Gal (α-Gal). This glycan is present in tick salivary proteins and on the surface of tick-borne pathogens such as Borrelia burgdorferi and Anaplasma phagocytophilum, the causative agents of Lyme disease and granulocytic anaplasmosis. Most α-Gal-sensitized individuals develop IgE specific against this glycan, but only a small fraction develop the AGS. This review summarizes our current understanding of ATR and its impact on the continuum α-Gal sensitization, allergy, and the AGS. We propose that the α-Gal-specific IgE response in humans is an evolutionary adaptation associated with ATR and allergic klendusity with the trade-off of developing AGS.

Masting by beech trees predicts the risk of Lyme disease.

BACKGROUND: The incidence of Lyme borreliosis and other tick-borne diseases is increasing in Europe and North America. There is currently much interest in identifying the ecological factors that determine the density of infected ticks as this variable determines the risk of Lyme borreliosis to vertebrate hosts, including humans. Lyme borreliosis is caused by the bacterium Borrelia burgdorferi sensu lato (s.l.) and in western Europe, the hard tick Ixodes ricinus is the most important vector. METHODS: Over a 15-year period (2004-2018), we monitored the monthly abundance of I. ricinus ticks (nymphs and adults) and their B. burgdorferi s.l. infection status at four different elevations on a mountain in western Switzerland. We collected climate variables in the field and from nearby weather stations. We obtained data on beech tree seed production (masting) from the literature, as the abundance of Ixodes nymphs can increase dramatically 2 years after a masting event. We used generalized linear mixed effects models and AIC-based model selection to identify the ecological factors that influence inter-annual variation in the nymphal infection prevalence (NIP) and the density of infected nymphs (DIN). RESULTS: We found that the NIP decreased by 78% over the study period. Inter-annual variation in the NIP was explained by the mean precipitation in the present year, and the duration that the DNA extraction was stored in the freezer prior to pathogen detection. The DIN decreased over the study period at all four elevation sites, and the decrease was significant at the top elevation. Inter-annual variation in the DIN was best explained by elevation site, year, beech tree masting index 2 years prior and the mean relative humidity in the present year. This is the first study in Europe to demonstrate that seed production by deciduous trees influences the density of nymphs infected with B. burgdorferi s.l. and hence the risk of Lyme borreliosis. CONCLUSIONS: Public health officials in Europe should be aware that masting by deciduous trees is an important predictor of the risk of Lyme borreliosis.

Suspicion of Lyme borreliosis in patients referred to an infectious diseases clinic: what did the patients really have?

OBJECTIVE: To evaluate the conditions behind the symptoms in patients with suspected Lyme borreliosis (LB) who were referred to an infectious diseases clinic. METHODS: In this retrospective, population-based study, we collected data from the medical records of all patients referred for infectious disease consultations in 2013 due to presumed LB from a population of 1.58 million. The patients were classified according to the certainty of LB on the basis of their symptoms, signs and laboratory results. Data on the outcomes and subsequent alternative diagnoses during the 4-year follow-up period were reviewed from all of the available patient records from public, private and occupational healthcare providers. RESULTS: A total of 256 patients (16/100 000) were referred as a result of suspicion of LB; 30 (12%) of 256 were classified with definite, 36 (14%) with probable and 65 (25%) with possible LB. LB was unlikely in 121 (47%) patients. A novel diagnosis was discovered in the background symptoms in 73 (29%) of patients. Previously diagnosed comorbidities caused at least some of the symptoms in 48 (19%) patients. Other explanations for symptoms were found in 81 (67%) of 121 of unlikely and 22 (34%) of 65 of possible LB patients. The spectrum of conditions behind the symptoms was quite broad and most often were musculoskeletal, neurological, psychological or functional disorders. CONCLUSIONS: LB was unlikely in half of the patients with presumed LB. In most cases the patients had other conditions that explained their symptoms.

Lactobacilli and other gastrointestinal microbiota of Peromyscus leucopus, reservoir host for agents of Lyme disease and other zoonoses in North America.

The cricetine rodent Peromyscus leucopus is an important reservoir for several human zoonoses, including Lyme disease, in North America. Akin to hamsters, the white-footed deermouse has been unevenly characterized in comparison to the murid Mus musculus. To further understanding of P. leucopus' total genomic content, we investigated gut microbiomes of an outbred colony of P. leucopus, inbred M. musculus, and a natural population of P. leucopus. Metagenome and whole genome sequencing were combined with microbiology and microscopy approaches. A focus was the genus Lactobacillus, four diverse species of which were isolated from forestomach and feces of colony P. leucopus. Three of the species-L. animalis, L. reuteri, and provisionally-named species "L. peromysci"-were identified in fecal metagenomes of wild P. leucopus but not discernibly in samples from M. musculus. L. johnsonii, the fourth species, was common in M. musculus but absent or sparse in wild P. leucopus. Also identified in both colony and natural populations were a Helicobacter sp. in feces but not stomach, and a Tritrichomonas sp. protozoan in cecum or feces. The gut metagenomes of colony P. leucopus were similar to those of colony M. musculus at the family or higher level and for major subsystems. But there were multiple differences between species and sexes within each species in their gut metagenomes at orthologous gene level. These findings provide a foundation for hypothesis-testing of functions of individual microbial species and for interventions, such as bait vaccines based on an autochthonous bacterium and targeting P. leucopus for transmission-blocking.

Tick-Borne Diseases in the United States.

BACKGROUND: Tick-borne diseases are an important cause of human morbidity and mortality in the United States. The past several decades have witnessed an increase in both the number of recognized tick-borne pathogens and the number of tick-borne disease cases, whereas tick surveys have revealed substantial geographic expansions of tick populations throughout the country. Multiple laboratory testing options exist for diagnosis of tick-borne diseases, including serology, microscopy, and molecular-based methods. The preferred approach varies by the specific disease, locally available test options, and the stage of illness at patient presentation. Accurate and timely detection of tick-borne illness is of utmost importance, as prompt treatment is strongly linked to better outcomes. CONTENT: This review covers the clinical manifestations and preferred diagnostic approaches for important bacterial, viral, and parasitic tick-borne diseases in the United States, including Lyme disease, tick-borne relapsing fever, anaplasmosis, ehrlichiosis, spotted fever rickettsioses, and babesiosis. Infection with emerging pathogens such as Borrelia miyamotoi, Powassan virus, Heartland virus, Colorado tick fever virus, and Bourbon virus are also covered. SUMMARY: Our understanding of tick-borne diseases in the United States continues to improve with the detection of novel pathogens and development of new diagnostic modalities. While conventional diagnostic methods, including serology and microscopy, will play an ongoing role in the diagnosis of tick-borne diseases, implementation of advanced molecular diagnostics will further broaden our understanding of these diseases by facilitating detection of emerging pathogens and providing more accurate and timely diagnosis.

Knowledge and Knowledge Needs about Lyme Disease among Occupational and Recreational Users of the Outdoors.

As the prevalence of Lyme disease increases across Canada, it is imperative that the educational needs of at-risk groups be identified. The current study compared the level of knowledge and the knowledge needs about Lyme disease among individuals that spend time outdoors for work and for recreational purposes. Between December 2018 and February 2019, a survey was distributed to outdoor organizations across New Brunswick, Canada. Within the current sample of 137 individuals, 36% spent time outdoors for their occupation and 64% for recreational activities. Results showed no significant difference between these groups with regard to their level of knowledge, perceived efficacy and performance of various methods of prevention, and educational needs. Overall, the entire sample reported a low level of knowledge about Lyme disease. Participants perceived each prevention behavior to be at least somewhat effective, and behaviors perceived to be more effective were more likely to be carried out, but the performance of the behaviors varied. The most frequently performed behaviors included wearing long pants and protective footwear. Participants identified several aspects of Lyme disease about which they would like to have more information. The findings call attention to the specific needs of at-risk groups that must be considered when developing educational interventions.

Measurement of Organ-Specific and Acute-Phase Blood Protein Levels in Early Lyme Disease.

Lyme disease results from infection of humans with the spirochete Borrelia burgdorferi. The first and most common clinical manifestation is the circular, inflamed skin lesion referred to as erythema migrans; later manifestations result from infections of other body sites. Laboratory diagnosis of Lyme disease can be challenging in patients with erythema migrans because of the time delay in the development of specific diagnostic antibodies against Borrelia. Reliable blood biomarkers for the early diagnosis of Lyme disease in patients with erythema migrans are needed. Here, we performed selected reaction monitoring, a targeted mass spectrometry-based approach, to measure selected proteins that (1) are known to be predominantly expressed in one organ (i.e., organ-specific blood proteins) and whose blood concentrations may change as a result of Lyme disease, or (2) are involved in acute immune responses. In a longitudinal cohort of 40 Lyme disease patients and 20 healthy controls, we identified 10 proteins with significantly altered serum levels in patients at the time of diagnosis, and we also developed a 10-protein panel identified through multivariate analysis. In an independent cohort of patients with erythema migrans, six of these proteins, APOA4, C9, CRP, CST6, PGLYRP2, and S100A9, were confirmed to show significantly altered serum levels in patients at time of presentation. Nine of the 10 proteins from the multivariate panel were also verified in the second cohort. These proteins, primarily innate immune response proteins or proteins specific to liver, skin, or white blood cells, may serve as candidate blood biomarkers requiring further validation to aid in the laboratory diagnosis of early Lyme disease.

Risk Factors for and Seroprevalence of Tickborne Zoonotic Diseases among Livestock Owners, Kazakhstan.

Crimean-Congo hemorrhagic fever (CCHF), Q fever, and Lyme disease are endemic to southern Kazakhstan, but population-based serosurveys are lacking. We assessed risk factors and seroprevalence of these zoonoses and conducted surveys for CCHF-related knowledge, attitudes, and practices in the Zhambyl region of Kazakhstan. Weighted seroprevalence for CCHF among all participants was 1.2%, increasing to 3.4% in villages with a known history of CCHF circulation. Weighted seroprevalence was 2.4% for Lyme disease and 1.3% for Q fever. We found evidence of CCHF virus circulation in areas not known to harbor the virus. We noted that activities that put persons at high risk for zoonotic or tickborne disease also were risk factors for seropositivity. However, recognition of the role of livestock in disease transmission and use of personal protective equipment when performing high-risk activities were low among participants.

Rodent Host Abundance and Climate Variability as Predictors of Tickborne Disease Risk 1 Year in Advance.

Using long-term data on incidences of Lyme disease and tickborne encephalitis, we showed that the dynamics of both diseases in central Europe are predictable from rodent host densities and climate indices. Our approach offers a simple and effective tool to predict a tickborne disease risk 1 year in advance.

Prevalence and determinants of persistent symptoms after treatment for Lyme borreliosis: study protocol for an observational, prospective cohort study (LymeProspect).

BACKGROUND: After antibiotic treatment of Lyme borreliosis, a subset of patients report persistent symptoms, also referred to as post-treatment Lyme disease syndrome. The reported prevalence of persistent symptoms varies considerably, and its pathophysiology is under debate. The LymeProspect study has been designed to investigate the prevalence, severity, and a wide range of hypotheses on the etiology of persistent symptoms among patients treated for Lyme borreliosis in the Netherlands. METHODS: LymeProspect is a prospective, observational cohort study among adults with proven or probable Lyme borreliosis, either erythema migrans or disseminated manifestations, included at the start of antibiotic treatment. During one year of follow-up, participants are subjected to questionnaires every three months and blood is collected repeatedly during the first three months. The primary outcome is the prevalence of persistent symptoms after treatment, assessed by questionnaires online focusing on fatigue (CIS, subscale fatigue severity), pain (SF-36, subscale pain) and neurocognitive dysfunction (CFQ). Potential microbiological, immunological, genetic, epidemiological and cognitive-behavioral determinants for persistent symptoms are secondary outcome measures. Control cohorts include patients with long-lasting symptoms and unconfirmed Lyme disease, population controls, and subjects having reported a tick bite not followed by Lyme borreliosis. DISCUSSION: This article describes the background and design of the LymeProspect study protocol. This study is characterized by a prospective, explorative and multifaceted design. The results of this study will provide insights into the prevalence and determinants of persistent symptoms after treatment for Lyme borreliosis, and may provide a rationale for preventive and treatment recommendations. TRIAL REGISTRATION: NTR4998 (Netherlands Trial Register). Date of registration: 13 February 2015.

Predicting the ligand-binding properties of Borrelia burgdorferi s.s. Bmp proteins in light of the conserved features of related Borrelia proteins.

Bacteria of the genus Borrelia cause vector-borne infections like the most important hard tick-borne disease in the northern hemisphere, Lyme borreliosis (LB), and soft tick or louse transmitted relapsing fevers (RF), prevalent in temperate and tropical areas. Borrelia burgdorferi sensu lato (s.l.) includes several genospecies and causes LB in humans. In infected patients, Borrelia burgdorferi sensu stricto (s.s.) expresses the BmpA, BmpB, BmpC and BmpD proteins. The role of these proteins in the pathogenesis of LB remains incompletely characterized, but they are, however, closely related to Treponema pallidum PnrA (Purine nucleoside receptor A), a substrate-binding lipoprotein of the ATP-binding cassette (ABC) transporter family preferentially binding purine nucleosides. Based on 3D homology modeling, the Bmp proteins share the typical fold of the substrate-binding protein family and the ligand-binding properties of BmpA, BmpB and BmpD are highly similar, whereas those of BmpC differ markedly. Nevertheless, these residues are highly conserved within the genus Borrelia and the inferred phylogenetic tree also reveals that the RF Borrelia lack BmpB proteins but has an additional Bmp protein (BmpA2) missing in LB-causing Borrelia burgdorferi s.l. Our results indicate that the Bmp proteins could bind nucleosides, although BmpC might have a different ligand-binding specificity and, therefore, a distinct function. Furthermore, the work provides a means for classifying the Bmp proteins and supports further elucidation of the roles of these proteins.

Horses as a Potential Reservoir of Lyme Borreliosis in Jeju-do, Korea.

Lyme borreliosis (LB) is the most common tick-borne infectious disease in North America, and it was designated as a national notifiable infectious disease in Korea in December 2010. While no cases in Jeju-do were recorded from 2012 to 2016, a recent survey reported that the seroprevalence of Borrelia burgdorferi using enzyme-linked immunosorbent assays in horses in Jeju-do was 19.0% (95% confidence interval, 12.0 to 28.3%). This fact suggests that horses may be a potential reservoir of LB in Jeju-do and that individuals in close contact with horses may be a high-risk group. Thus, a serological study in this high-risk group is urgently needed.

Climate change and skin disease.

Despite commanding essentially universal scientific consensus, climate change remains a divisive and poorly understood topic in the United States. Familiarity with this subject is not just for climate scientists. The impact of climate change on human morbidity and mortality may be considerable; thus, physicians also should be knowledgeable in this realm. Climate change science can seem opaque and inferential, creating fertile ground for political polemics and undoubtedly contributing to confusion among the general public. This puts physicians in a pivotal position to facilitate a practical understanding of climate change in the public sphere by discussing changes in disease patterns and their possible relationship to a changing climate. This article provides a background on climate change for dermatologists and highlights how climate change may impact the management of skin disease across the United States.

Reconciling the Entomological Hazard and Disease Risk in the Lyme Disease System.

Lyme disease (LD) is a commonly cited model for the link between habitat loss and/or fragmentation and disease emergence, based in part on studies showing that forest patch size is negatively related to LD entomological risk. An equivalent relationship has not, however, been shown between patch size and LD incidence (LDI). Because entomological risk is measured at the patch scale, while LDI is generally assessed in relation to aggregate landscape statistics such as forest cover, we posit that the contribution of individual patches to human LD risk has not yet been directly evaluated. We design a model that directly links theoretical entomological risk at the patch scale to larger-scale epidemiological data. We evaluate its predictions for relative LD risk in artificial landscapes with varying composition and configuration, and test its ability to predict countywide LDI in a 12-county region of New York. On simulated landscapes, we find that the model predicts a unimodal relationship between LD incidence and forest cover, mean patch size, and mean minimum distance (a measure of isolation), and a protective effect for percolation probability (a measure of connectivity). In New York, risk indices generated by this model are significantly related to countywide LDI. The results suggest that the lack of concordance between entomological risk and LDI may be partially resolved by this style of model.

Autoimmunity against a glycolytic enzyme as a possible cause for persistent symptoms in Lyme disease.

Some patients with a history of Borrelia burgdorferi infection develop a chronic symptomatology characterized by cognitive deficits, fatigue, and pain, despite antibiotic treatment. The pathogenic mechanism that underlines this condition, referred to as post-treatment Lyme disease syndrome (PTLDS), is currently unknown. A debate exists about whether PTLDS is due to persistent infection or to post-infectious damages in the immune system and the nervous system. We present the case of a patient with evidence of exposure to Borrelia burgdorferi sl and a long history of debilitating fatigue, cognitive abnormalities and autonomic nervous system issues. The patient had a positive Western blot for anti-basal ganglia antibodies, and the autoantigen has been identified as γ enolase, the neuron-specific isoenzyme of the glycolytic enzyme enolase. Assuming Borrelia own surface exposed enolase as the source of this autoantibody, through a mechanism of molecular mimicry, and given the absence of sera reactivity to α enolase, a bioinformatical analysis was carried out to identify a possible cross-reactive conformational B cell epitope, shared by Borrelia enolase and γ enolase, but not by α enolase. Taken that evidence, we hypothesize that this autoantibody interferes with glycolysis in neuronal cells, as the physiological basis for chronic symptoms in at least some cases of PTLDS. Studies investigating on the anti-γ enolase and anti-Borrelia enolase antibodies in PTLDS are needed to confirm our hypotheses.

Tick Talk: Tick-borne Diseases of South Dakota.

In addition to being a nuisance, ticks can carry disease. This article presents a brief review of ticks and associated tick-borne disease relevant to South Dakota and surrounding regions. Tick-borne diseases of special relevance in South Dakota include tularemia, Rocky Mountain spotted fever, and Lyme disease. A number of others may also be encountered in the state as well. Prompt treatment of suspected cases is important to ensure a successful recovery, and tick-avoidance measures can reduce the risks of acquiring them. Most of these conditions are nationally reportable infectious diseases.

Borrelia infection and risk of celiac disease.

BACKGROUND: Environmental factors, including infectious agents, are speculated to play a role in the rising prevalence and the geographic distribution of celiac disease, an autoimmune disorder. In the USA and Sweden where the regional variation in the frequency of celiac disease has been studied, a similarity with the geographic distribution of Lyme disease, an emerging multisystemic infection caused by Borrelia burgdorferi spirochetes, has been found, thus raising the possibility of a link. We aimed to determine if infection with Borrelia contributes to an increased risk of celiac disease. METHODS: Biopsy reports from all of Sweden's pathology departments were used to identify 15,769 individuals with celiac disease. Through linkage to the nationwide Patient Register, we compared the rate of earlier occurrence of Lyme disease in the patients with celiac disease to that in 78,331 matched controls. To further assess the temporal relationship between Borrelia infection and celiac disease, we also examined the risk of subsequent Lyme disease in patients with a diagnosis of celiac disease. RESULTS: Twenty-five individuals (0.16%) with celiac disease had a prior diagnosis of Lyme disease, whereas 79 (0.5%) had a subsequent diagnosis of Lyme disease. A modest association between Lyme disease and celiac disease was seen both before (odds ratio, 1.61; 95% confidence interval (CI), 1.06-2.47) and after the diagnosis of celiac disease (hazard ratio, 1.82; 95% CI, 1.40-2.35), with the risk of disease being highest in the first year of follow-up. CONCLUSIONS: Only a minor fraction of the celiac disease patient population had a prior diagnosis of Lyme disease. The similar association between Lyme disease and celiac disease both before and after the diagnosis of celiac disease is strongly suggestive of surveillance bias as a likely contributor. Taken together, the data indicate that Borrelia infection is not a substantive risk factor in the development of celiac disease.

Predicting the risk of Lyme borreliosis after a tick bite, using a structural equation model.

BACKGROUND: Understanding and quantification of the risk of Lyme borreliosis after a tick bite can aid development of prevention strategies against Lyme borreliosis. METHODS: We used 3,525 single tick bite reports from three large prospective studies on the transmission risk of tick-borne pathogens to humans, with 50 reports of Lyme borreliosis during the follow-up period, among 1,973 reports with known outcome. A structural equation model was applied to estimate the risk of Lyme borreliosis after a tick bite, and quantify the influence of: developmental stage of the tick, detection of Borrelia burgdorferi s.l. DNA in the tick by PCR, tick engorgement, patient-estimated duration of tick attachment, and patient age. RESULTS: The overall risk of developing Lyme borreliosis after a tick bite was 2.6% (95%CI 1.4-5.1). The risk increased with: - Tick engorgement: 1.4% (95%CI 0.7%-2.3%) for low engorgement to 5.5% (95%CI 2.8%-9.2%) for substantially engorged ticks;- Rising patient-estimated tick attachment duration: 2.0% (95%CI 1.3%-2.8%) after <12 hours, to 5.2% (95%CI 3.0%-8.9%) after ≥4 days;- Detection of Borrelia burgdorferi s.l. DNA in ticks: 6.7% (95%CI 3.6%-13.5%), versus 1.4% (95%CI 0.7%-2.9%) when ticks tested negative.The highest observed risk of Lyme borreliosis was 14.4% (95%CI 6.8%-24.6%) after one tick bite of a substantially engorged tick that tested positive for Borrelia burgdorferi s.l. DNA, which corresponds to one new case of Lyme borreliosis per 7 (95%CI 4-15) of such tick bites. CONCLUSIONS: An individual's risk of Lyme borreliosis after a tick bite can be predicted with tick engorgement, patient-estimated duration of tick attachment, and detection of Borrelia burgdorferi s.l. DNA in the tick.