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One Health (Amsterdam, Netherlands) Jun 2024Tick-borne flaviviruses and spp. are globally spread pathogens of zoonotic potential that are maintained by a transmission cycle at the interface between ticks and... (Review)
Review
Tick-borne flaviviruses and spp. are globally spread pathogens of zoonotic potential that are maintained by a transmission cycle at the interface between ticks and vertebrate hosts, mainly wild animals. Aside data on pathogen burden in ticks, information on the status of various hosts relative to infection is important to acquire. We reviewed how those infections have been studied in wildlife host species in the field to discuss how collected data provided relevant epidemiological information and to identify needs for further studies. The literature was screened for observational studies on pathogen or antibody detection for tick-borne spp. and flaviviruses in wildlife host animals. Overall, spp. were more studied (73% of case studies, representing 297 host species) than flaviviruses (27% of case studies, representing 114 host species). Studies on both spp. and flaviviruses focused mainly on the same species, namely bank vole and yellow-necked mouse. Most studies were order-specific and cross-sectional, reporting prevalence at various locations, but with little insight into the underlying epidemiological dynamics. Host species with potential to act as reservoir hosts of these pathogens were neglected, notably birds. We highlight the necessity of collecting both demographics and infection data in wildlife studies, and to consider communities of species, to better estimate zoonotic risk potential in the One Health context.
PubMed: 38746540
DOI: 10.1016/j.onehlt.2024.100747 -
BioRxiv : the Preprint Server For... May 2024ticks are an important vector for at least six tick-borne human pathogens, including the predominant North American Lyme disease spirochete . The ability for these...
UNLABELLED
ticks are an important vector for at least six tick-borne human pathogens, including the predominant North American Lyme disease spirochete . The ability for these ticks to survive in nature is credited, in part, to their ability to feed on a variety of hosts without excessive activation of the proinflammatory branch of the vertebrate immune system. While the ability for nymphal ticks to feed on a variety of hosts has been well-documented, the host-parasite interactions between larval and different vertebrate hosts is relatively unexplored. Here we report on the changes in the vertebrate transcriptome present at the larval tick bite site using the natural host deermouse, a non-natural rodent host (BALB/c), and humans. We note substantially less evidence of activation of canonical proinflammatory pathways in compared to BALB/c mice and pronounced evidence of inflammation in humans. Pathway enrichment analyses revealed a particularly strong signature of interferon gamma, tumor necrosis factor, and interleukin 1 signaling at the BALB/c and human tick bite site. We also note that bite sites on BALB/c mice and humans, but not deermice, show activation of wound-healing pathways. These data provide molecular evidence of the coevolution between larval and as well as expand our overall understanding of feeding.
SIGNIFICANCE
tick bites expose humans to numerous diseases in North America. While larval tick feeding enables pathogens to enter the tick population and eventually spread to humans, how larval ticks interact with mammals has been understudied compared to other tick stages. Here we examined the transcriptomic response of a natural rodent host ( ), a non-native rodent host ( ), and an incidental host (humans). We find that there are differences in how all three species respond to larval , with the natural host producing the smallest transcriptomic signature of a canonical proinflammatory immune response and the incidental human host producing the most robust signature of inflammation in response to the larval tick. These data expand our understanding of the pressures on ticks in the wild and inform our ability to model these interactions in laboratory settings.
PubMed: 38746284
DOI: 10.1101/2024.05.02.592193 -
BioRxiv : the Preprint Server For... Apr 2024Innate immunity, the first line of defense against pathogens, relies on efficient elimination of invading agents by phagocytes. In the co-evolution of host and pathogen,...
Innate immunity, the first line of defense against pathogens, relies on efficient elimination of invading agents by phagocytes. In the co-evolution of host and pathogen, pathogens developed mechanisms to dampen and evade phagocytic clearance. Here, we report that bacterial pathogens can evade clearance by macrophages through mimicry at the mammalian anti-phagocytic "don't eat me" signaling axis between CD47 (ligand) and SIRPα (receptor). We identified a protein, P66, on the surface of that, like CD47, is necessary and sufficient to bind the macrophage receptor SIRPα. Expression of the gene encoding the protein is required for bacteria to bind SIRPα or a high-affinity CD47 reagent. Genetic deletion of increases phagocytosis by macrophages. Blockade of P66 during infection promotes clearance of the bacteria. This study demonstrates that mimicry of the mammalian anti-phagocytic protein CD47 by inhibits macrophage-mediated bacterial clearance. Such a mechanism has broad implications for understanding of host-pathogen interactions and expands the function of the established innate immune checkpoint receptor SIRPα. Moreover, this report reveals P66 as a novel therapeutic target in the treatment of Lyme Disease.
PubMed: 38746193
DOI: 10.1101/2024.04.29.591704 -
Scientific Reports May 2024Multiple sclerosis (MS) is a chronic, demyelinating disease of the central nervous system that affects mainly young people. It is believed that the autoimmune process...
Multiple sclerosis (MS) is a chronic, demyelinating disease of the central nervous system that affects mainly young people. It is believed that the autoimmune process observed in the pathogenesis of MS is influenced by a complex interaction between genetic and environmental factors, including infectious agents. The results of this study suggest the protective role of Toxoplasma gondii infections in MS. Interestingly, high Toxoplasma IgM seropositivity in MS patients receiving immunomodulatory drugs (IMDs) was identified. On the other hand, Borrelia infections seem to be positively associated with MS. Although the interpretation of our results is limited by the retrospective nature of the studies, the results strongly indicate that further experimental and clinical studies are needed to explain the role of infectious agents in the development and pathophysiological mechanisms of MS.
Topics: Humans; Multiple Sclerosis; Toxoplasmosis; Poland; Seroepidemiologic Studies; Female; Toxoplasma; Male; Adult; Lyme Disease; Borrelia burgdorferi; Middle Aged; Immunoglobulin M; Retrospective Studies; Young Adult
PubMed: 38744898
DOI: 10.1038/s41598-024-61714-y -
Frontiers in Immunology 2024Relapsing fever (RF) remains a neglected human disease that is caused by a number of diverse pathogenic () species. Characterized by high cell densities in human blood,...
INTRODUCTION
Relapsing fever (RF) remains a neglected human disease that is caused by a number of diverse pathogenic () species. Characterized by high cell densities in human blood, relapsing fever spirochetes have developed plentiful strategies to avoid recognition by the host defense mechanisms. In this scenario, spirochetal lipoproteins exhibiting multifunctional binding properties in the interaction with host-derived molecules are known to play a key role in adhesion, fibrinolysis and complement activation.
METHODS
Binding of CihC/FbpC orthologs to different human proteins and conversion of protein-bound plasminogen to proteolytic active plasmin were examined by ELISA. To analyze the inhibitory capacity of CihC/FbpC orthologs on complement activation, a microtiter-based approach was performed. Finally, AlphaFold predictions were utilized to identified the complement-interacting residues.
RESULTS AND DISCUSSION
Here, we elucidate the binding properties of CihC/FbpC-orthologs from distinct RF spirochetes including , , , and to human fibronectin, plasminogen, and complement component C1r. All CihC/FbpC-orthologs displayed similar binding properties to fibronectin, plasminogen, and C1r, respectively. Functional studies revealed a dose dependent binding of plasminogen to all borrelial proteins and conversion to active plasmin. The proteolytic activity of plasmin was almost completely abrogated by tranexamic acid, indicating that lysine residues are involved in the interaction with this serine protease. In addition, a strong inactivation capacity toward the classical pathway could be demonstrated for the wild-type CihC/FbpC-orthologs as well as for the C-terminal CihC fragment of . Pre-incubation of human serum with borrelial molecules except CihC/FbpC variants lacking the C-terminal region protected serum-susceptible cells from complement-mediated lysis. Utilizing AlphaFold2 predictions and existing crystal structures, we mapped the putative key residues involved in C1r binding on the CihC/FbpC orthologs attempting to explain the relatively small differences in C1r binding affinity despite the substitutions of key residues. Collectively, our data advance the understanding of the multiple binding properties of structural and functional highly similar molecules of relapsing fever spirochetes proposed to be involved in pathogenesis and virulence.
Topics: Humans; Fibrinolysis; Borrelia; Relapsing Fever; Plasminogen; Protein Binding; Bacterial Proteins; Complement Activation; Immune Evasion; Bacterial Adhesion; Host-Pathogen Interactions; Fibronectins; Fibrinolysin; Complement System Proteins
PubMed: 38726006
DOI: 10.3389/fimmu.2024.1390468 -
Cureus Apr 2024Infection with spirochetes can cause Lyme neuroborreliosis (LNB). Neuroborreliosis presenting as encephalitis is a rare manifestation. We present a 72-year-old...
Infection with spirochetes can cause Lyme neuroborreliosis (LNB). Neuroborreliosis presenting as encephalitis is a rare manifestation. We present a 72-year-old male patient hospitalized after three days of confusion and altered mental status. Initial computerized tomography (CT) and magnetic resonance imaging (MRI) of the brain were both unremarkable. Lumbar puncture showed an elevated number of white blood cells, elevated protein, and normal glucose levels in the cerebrospinal fluid (CSF), normal electroencephalogram (EEG), and negative tests for common microorganisms in the CSF. The patient received treatment with acyclovir and ceftriaxone. Lumbar puncture repeated on day 16 showed a decreasing number of white blood cells. A repeated MRI showed white matter edema, interpreted as encephalitis, while a repeated EEG showed signs of a non-specific cerebral lesion. The first lumbar puncture revealed intrathecal immunoglobulin M (IgM) antibodies against and was positive for DNA using real-time PCR, and the following lumbar puncture showed both IgM and IgG intrathecal antibody production. These results thus confirmed the diagnosis of Lyme encephalitis. The patient improved clinically and was discharged after treatment with ceftriaxone for three weeks. Encephalitis due to LNB should be considered as a differential diagnosis in cases with unexplained neurological symptoms. Changes in MRI and/or EEG might occur late in the course of the disease, underlining the need for repeated tests in unresolved cases.
PubMed: 38725777
DOI: 10.7759/cureus.57882 -
Ticks and Tick-borne Diseases Jul 2024Definite diagnosis of Lyme neuroborreliosis (LNB) requires investigation of serum and cerebrospinal fluid (CSF). Thus, lumbar puncture is necessary, and requires...
Definite diagnosis of Lyme neuroborreliosis (LNB) requires investigation of serum and cerebrospinal fluid (CSF). Thus, lumbar puncture is necessary, and requires administration of sedating drugs in children. This study aimed to investigate if a pattern of different inflammatory biomarkers in serum could contribute to the selection of children for lumbar puncture in suspected LNB. Patients were included from a cohort of children who was previously investigated for LNB including serum and CSF sampling during the years 2010-2014. The multiplex proximity extension assay (PEA) inflammation panel Target 96 (Olink Bioscience, Uppsala, Sweden) was used to examine 92 biomarkers in serum. Based on the presence of CSF pleocytosis and Borrelia-specific antibodies, patients were divided into a definite LNB group (n=61) and a non-LNB control group (n=58). Following PEA and statistical analysis with multivariate logistic regression, five biomarkers remained significant (p < 0.001), which were included in a calculation of protein index. The index biomarkers were CST5, IL-15RA, CXCL10, DNER and CX3CL1. A receiver operating characteristic curve was constructed from the index, which showed an 80 % sensitivity and 81 % specificity. Area under the curve was 0.889. We offer evidence that, with further refinements, patterns of serum biomarkers might help identify those children more or less likely to have LNB, perhaps ultimately decreasing the need for lumbar punctures.
Topics: Humans; Lyme Neuroborreliosis; Child; Biomarkers; Male; Female; Adolescent; Child, Preschool
PubMed: 38723400
DOI: 10.1016/j.ttbdis.2024.102349 -
PloS One 2024Lyme disease is the most common wildlife-to-human transmitted disease reported in North America. The study of this disease requires an understanding of the ecology of...
Lyme disease is the most common wildlife-to-human transmitted disease reported in North America. The study of this disease requires an understanding of the ecology of the complex communities of ticks and host species involved in harboring and transmitting this disease. Much of the ecology of this system is well understood, such as the life cycle of ticks, and how hosts are able to support tick populations and serve as disease reservoirs, but there is much to be explored about how the population dynamics of different host species and communities impact disease risk to humans. In this study, we construct a stage-structured, empirically-informed model with host dynamics to investigate how host population dynamics can affect disease risk to humans. The model describes a tick population and a simplified community of three host species, where primary nymph host populations are made to fluctuate on an annual basis, as commonly observed in host populations. We tested the model under different environmental conditions to examine the effect of environment on the interactions of host dynamics and disease risk. Results show that allowing for host dynamics in the model reduces mean nymphal infection prevalence and increases the maximum annual prevalence of nymphal infection and the density of infected nymphs. Effects of host dynamics on disease measures of nymphal infection prevalence were nonlinear and patterns in the effect of dynamics on amplitude in nymphal infection prevalence varied across environmental conditions. These results highlight the importance of further study of the effect of community dynamics on disease risk. This will involve the construction of further theoretical models and collection of robust field data to inform these models. With a more complete understanding of disease dynamics we can begin to better determine how to predict and manage disease risk using these models.
Topics: Lyme Disease; Animals; Humans; Population Dynamics; Ixodes; Models, Theoretical; Ticks; Models, Biological; Borrelia burgdorferi; Host-Parasite Interactions; Nymph
PubMed: 38722910
DOI: 10.1371/journal.pone.0302874 -
Nature Communications May 2024The incidence of Lyme borreliosis has risen, accompanied by persistent symptoms. The innate immune system and related cytokines are crucial in the host response and...
The incidence of Lyme borreliosis has risen, accompanied by persistent symptoms. The innate immune system and related cytokines are crucial in the host response and symptom development. We characterized cytokine production capacity before and after antibiotic treatment in 1,060 Lyme borreliosis patients. We observed a negative correlation between antibody production and IL-10 responses, as well as increased IL-1Ra responses in patients with disseminated disease. Genome-wide mapping the cytokine production allowed us to identify 34 cytokine quantitative trait loci (cQTLs), with 31 novel ones. We pinpointed the causal variant at the TLR1-6-10 locus and validated the regulation of IL-1Ra responses at transcritpome level using an independent cohort. We found that cQTLs contribute to Lyme borreliosis susceptibility and are relevant to other immune-mediated diseases. Our findings improve the understanding of cytokine responses in Lyme borreliosis and provide a genetic map of immune function as an expanded resource.
Topics: Lyme Disease; Humans; Quantitative Trait Loci; Cytokines; Male; Female; Interleukin-10; Adult; Genome-Wide Association Study; Middle Aged; Interleukin 1 Receptor Antagonist Protein; Borrelia burgdorferi; Anti-Bacterial Agents; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease; Aged
PubMed: 38714679
DOI: 10.1038/s41467-024-47505-z -
Journal of Microbiological Methods May 2024Reliable detection of bacteria belonging to the Borrelia burgdorferi sensu lato species complex in vertebrate reservoirs, tick vectors, and patients is key to answer...
Reliable detection of bacteria belonging to the Borrelia burgdorferi sensu lato species complex in vertebrate reservoirs, tick vectors, and patients is key to answer questions regarding Lyme borreliosis epidemiology. Nevertheless, the description of characteristics of qPCRs for the detection of B. burgdorferi s. l. are often limited. This study covers the development and validation of two duplex taqman qPCR assays used to target four markers on the chromosome of genospecies of B. burgdorferi s. l. Analytical specificity was determined with a panel of spirochete strains. qPCR characteristics were specified using water or tick DNA spiked with controlled quantities of the targeted DNA sequences of B. afzelii, B. burgdorferi sensu stricto or B. bavariensis. The effectiveness of detection results was finally evaluated using DNA extracted from ticks and biopsies from mammals whose infectious status had been determined by other detection assays. The developed qPCR assays allow exclusive detection of B. burgdorferi s. l. with the exception of the M16 marker which also detect relapsing fever Borreliae. The limit of detection is between 10 and 40 copies per qPCR reaction depending on the sample type, the B. burgdorferi genospecies and the targeted marker. Detection tests performed on various kind of samples illustrated the accuracy and robustness of our qPCR assays. Within the defined limits, this multi-target qPCR method allows a versatile detection of B. burgdorferi s. l., regardless of the genospecies and the sample material analyzed, with a sensitivity that would be compatible with most applications and a reproducibility of 100% under measurement conditions of limits of detection, thereby limiting result ambiguities.
PubMed: 38714225
DOI: 10.1016/j.mimet.2024.106941