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Borrelia , spirochetes transmitted by ticks, are the etiological agents of numerous multisystemic diseases, such as Lyme borreliosis (LB) and tick-borne relapsing fever (TBRF). This study focuses on two surface proteins from two Borrelia subspecies involved in these diseases: CspZ, expressed by Borrelia burgdorferi sensu stricto (also named BbCRASP-2 for complement regulator-acquiring surface protein 2), and the factor H binding A (FhbA), expressed by Borrelia hermsii. Numerous subspecies of Borrelia , including these latter, are able to evade the immune defenses of a variety of potential vertebrate hosts in a number of ways. In this context, previous data suggested that both surface proteins play a role in the immune evasion of both Borrelia subspecies by interacting with key regulators of the alternative pathway of the human complement system, factor H (FH) and FH-like protein 1 (FHL-1). The recombinant proteins, CspZ and FhbA, were expressed in Escherichia coli and purified by one-step metal-affinity chromatography, with yields of 15 and 20 mg or pure protein for 1 L of cultured bacteria, respectively. The purity was evaluated by SDS-PAGE and HPLC and is close to about 95%. The mass of CspZ and FhbA was checked by mass spectrometry (MS). Proper folding of CspZ and FhbA was confirmed by circular dichroism (CD), and their biological activity, namely their interaction with purified FH from human serum (recombinant FH 15-20  and recombinant FHL-1), was characterized by SPR. Such a study provides the basis for the biochemical characterization of the studied proteins and their biomolecular interactions which is a necessary prerequisite for the development of new approaches to improve the current diagnosis of LB and TBRF. Key points • DLS, CD, SEC-MALS, NMR, HPLC, and MS are tools for protein quality assessment • Borrelia spp. possesses immune evasion mechanisms, including human host complement • CspZ and FhbA interact with high affinity (pM to nM) to human FH and rFHL-1 Graphical Abstract

Lyme borreliosis is the most common tick-borne disease in the northern hemisphere. It is a multisystem disease caused by Borrelia burgdorferi sensu lato genospecies and characterised by tissue localisation and low spirochaetaemia. In this study we aimed to describe a novel Borrelia species causing Lyme borreliosis in the USA. At the Mayo clinic, from 2003 to 2014, we tested routine clinical diagnostic specimens from patients in the USA with PCR targeting the oppA1 gene of B burgdorferi sensu lato. We identified positive specimens with an atypical PCR result (melting temperature outside of the expected range) by sequencing, microscopy, or culture. We collected Ixodes scapularis ticks from regions of suspected patient tick exposure and tested them by oppA1 PCR. 100 545 specimens were submitted by physicians for routine PCR from Jan 1, 2003 to Sept 30, 2014. From these samples, six clinical specimens (five blood, one synovial fluid) yielded an atypical oppA1 PCR product, but no atypical results were detected before 2012. Five of the six patients with atypical PCR results had presented with fever, four had diffuse or focal rash, three had symptoms suggestive of neurological inclusion, and two were admitted to hospital. The sixth patient presented with knee pain and swelling. Motile spirochaetes were seen in blood samples from one patient and cultured from blood samples from two patients. Among the five blood specimens, the median oppA1 copy number was 180 times higher than that in 13 specimens that tested positive for B burgdorferi sensu stricto during the same time period. Multigene sequencing identified the spirochaete as a novel B burgdorferi sensu lato genospecies. This same genospecies was detected in ticks collected at a probable patient exposure site. We describe a new pathogenic Borrelia burgdorferi sensu lato genospecies (candidatus Borrelia mayonii) in the upper midwestern USA, which causes Lyme borreliosis with unusually high spirochaetaemia. Clinicians should be aware of this new B burgdorferi sensu lato genospecies, its distinct clinical features, and the usefulness of oppA1 PCR for diagnosis. US Centers for Disease Control and Prevention Epidemiology and Laboratory Capacity for Infectious Diseases (ELC) Cooperative Agreement and Mayo Clinic Small Grant programme.

A national crowdsourcing-based tick collection campaign was organized in 2015 with the objective of producing novel data on tick distribution and tick-borne pathogens in Finland. Nearly 20 000 Ixodes ticks were collected. The collected material revealed the nationwide distribution of I. persulcatus for the first time and a shift northwards in the distribution of I. ricinus in Finland. A subset of 2038 tick samples containing both species was screened for Borrelia burgdorferi sensu lato (the prevalence was 14.2% for I. ricinus and 19.8% for I. persulcatus), B. miyamotoi (0.2% and 0.4%, respectively) and tick-borne encephalitis virus (TBEV; 0.2% and 3.0%, respectively). We also report new risk areas for TBEV in Finland and, for the first time, the presence of B. miyamotoi in ticks from mainland Finland. Most importantly, our study demonstrates the overwhelming power of citizen science in accomplishing a collection effort that would have been impossible with the scientific community alone. Emerging Microbes & Infections (2017) 6, e31; doi: 10.1038/emi.2017.17 ; published online 10 May 2017

The bacterial flagellar motor can rotate in counterclockwise (CCW) or clockwise (CW) senses, and transitions are controlled by the phosphorylated form of the response regulator CheY (CheY-P). To dissect the mechanism underlying flagellar rotational switching, we use Borrelia burgdorferi as a model system to determine high-resolution in situ motor structures in cheX and cheY3 mutants, in which motors are locked in either CCW or CW rotation. The structures showed that CheY3-P interacts directly with a switch protein, FliM, inducing a major remodeling of another switch protein, FliG2, and altering its interaction with the torque generator. Our findings lead to a model in which the torque generator rotates in response to an inward flow of H+ driven by the proton motive force, and conformational changes in FliG2 driven by CheY3-P allow the switch complex to interact with opposite sides of the rotating torque generator, facilitating rotational switching.In situ cryo-ET analyses of Borrelia burgdorferi flagellar motors locked in clockwise or counterclockwise rotation provide insights into rotational switching.

Background Lyme borreliosis (LB), the most common vector-borne disease in the Northern Hemisphere, is caused by a multitude of pathogenic Borrelia burgdorferi sensu lato (sl) species endemic to northern, western, and central regions of Europe. We utilized whole genome sequencing (WGS) to characterize the genetic diversity of 130 clinical B. burgdorferi sl isolates collected from LB cases in the Netherlands between 1988 and 2023, the majority of which were B. afzelii . Results WGS analysis revealed significant diversity, including 29 different multi-locus sequence types (MLSTs) across four genospecies. Plasmids from B. garinii and B. bavariensis were found to exhibit greater sequence diversity than those from B. burgdorferi sensu stricto and B. afzelii . We further characterized the Borrelia membrane protein antigens OspA, OspC and DbpA for sequence diversity and correlation with LB disease state. Conclusions This large-scale genomic analysis of clinical Dutch B. burgdorferi sl isolates furthers our understanding of LB and may indicate potential coverage for LB vaccine candidates in clinical development.

Key Points Evolutionary ecology is an amalgamation of evolutionary biology and ecology, which considers evolutionary relationships and genetic changes in species or populations as well as their interactions with each other and with the environment. Two questions are central to the scientific debate in evolutionary ecology: how do population fluctuations arise and how is diversity generated and maintained? Despite different terminology, the same fundamental questions are at the centre of contemporary infectious disease epidemiology. The evolutionary ecology of many emerging infectious diseases, in particular vector-borne zoonoses, is poorly understood. For directly transmitted pathogens, the term 'strain space' has been coined, the geometry of which is described by two processes, host immunity and the rate of genetic change of the pathogen. Many emerging infectious diseases are transmitted by vectors, mainly ticks and insects, and for these, vector-related processes might further define the strain space. Therefore, it is essential to understand vector-related processes to decide to what extent the principles that are common to directly transmitted pathogens can be extrapolated to vector-borne pathogens. Current models of vector-borne zoonoses are theoretical, except for those that aim to capture the spatial?temporal distribution of such systems based on statistical, pattern-matching approaches. The scientific community has now realized that the development and parameterization of biological, process-based models of vector-borne diseases are timely, feasible and important tasks. In this Review, we aim to set out the framework needed to develop biological, process-based models of vector-borne zoonoses, using Borrelia burgdorferi sensu lato (s.l.), the spirochaete agent of Lyme borreliosis, as an example. By comparing different natural transmission cycles, and by reviewing advances in our understanding of spirochaete transmission, we identify key processes that drive the evolutionary ecology of B. burgdorferi s.l., and which must be accounted for in mathematical models. We put forward hypotheses on how B. burgdorferi s.l. populations respond to these processes and discuss the impact of the host community on this zoonosis through the 'dilution effect' and 'multiple niche polymorphism'. We highlight possible ecological parallels among the different members of the B. burgdorferi s.l. species complex and other important vector-borne microparasites, which might indicate that there are common principles in their evolution. Statistical models of vector-borne zoonoses can be useful, but models based on fundamental biological processes are thought to be more powerful in deciphering the mechanisms responsible for the observed distribution patterns. Here, Kurtenbach and colleagues describe the framework needed to develop models of vector-borne zoonoses based on biological processes, using Lyme borreliosis as an example. The evolutionary ecology of many emerging infectious diseases, particularly vector-borne zoonoses, is poorly understood. Here, we aim to develop a biological, process-based framework for vector-borne zoonoses, using Borrelia burgdorferi sensu lato (s.l.), the causative agent of Lyme borreliosis in humans, as an example. We explore the fundamental biological processes that operate in this zoonosis and put forward hypotheses on how extrinsic cues and intrinsic dynamics shape B. burgdorferi s.l. populations. Additionally, we highlight possible epidemiological parallels between B. burgdorferi s.l. and other vector-borne zoonotic pathogens, including West Nile virus.

Borrelia burgdorferi is the causative agent of Lyme disease and is transmitted to vertebrate hosts by Ixodes spp. ticks. The spirochaete relies heavily on its arthropod host for basic metabolic functions and has developed complex interactions with ticks to successfully colonize, persist and, at the optimal time, exit the tick. For example, proteins shield spirochaetes from immune factors in the bloodmeal and facilitate the transition between vertebrate and arthropod environments. On infection, B. burgdorferi induces selected tick proteins that modulate the vector gut microbiota towards an environment that favours colonization by the spirochaete. Additionally, the recent sequencing of the Ixodes scapularis genome and characterization of tick immune defence pathways, such as the JAK–STAT, immune deficiency and cross-species interferon-γ pathways, have advanced our understanding of factors that are important for B. burgdorferi persistence in the tick. In this Review, we summarize interactions between B. burgdorferi and I. scapularis during infection, as well as interactions with tick gut and salivary gland proteins important for establishing infection and transmission to the vertebrate host.Borrelia burgdorferi has a complex life cycle with several different hosts, causing Lyme disease when it infects humans. In this Review, Fikrig and colleagues discuss how B. burgdorferi infects and interacts with its tick vector to ensure onward transmission.

Lyme disease (also called Lyme borreliosis in Europe), a condition caused by spirochete bacteria of the genus Borrelia , transmitted by hard-bodied Ixodes ticks, is currently the most prevalent and rapidly expanding tick-borne disease in the United States and Europe. Borrelia interspecies and intraspecies genome comparisons of Lyme disease-related bacteria are essential to reconstruct their evolutionary origins, track epidemiological spread, identify molecular mechanisms of human pathogenicity, and design molecular and ecological approaches to disease prevention, diagnosis, and treatment. These Lyme disease-associated bacteria harbor complex genomes that encode many genes that do not have homologs in other organisms and are distributed across multiple linear and circular plasmids. The functional significance of most of the plasmid-borne genes and the multipartite genome organization itself remains unknown. Here we sequenced, assembled, and analyzed whole genomes of 47 Borrelia isolates from around the world, including multiple isolates of the human pathogenic species. Our analysis elucidates the evolutionary origins, historical migration, and sources of genomic variability of these clinically important pathogens. We have developed web-based software tools (BorreliaBase.org) to facilitate dissemination and continued comparative analysis of Borrelia genomes to identify determinants of human pathogenicity.

Background Ticks are important vectors of zoonotic pathogens, with Ixodes ricinus being the most abundant and main vector in Europe of Borrelia burgdorferi sensu lato (s.l.), the causative agent of Lyme borreliosis. Both vector and reservoir hosts are dependent on habitat structure, which is anthropogenically influenced by land use intensity. This study aimed to analyse the prevalence of B. burgdorferi s.l. and their genodiversity in ticks along a land use gradient in grassland and forest in Central Germany. Methods Ticks were collected from 25 grassland and 25 forest sites by using the flagging method and tested for Borrelia   spp. using real-time polymerase chain reaction. Positive samples were further analysed by using multi-locus sequence typing to identify the exact B. burgdorferi s.l. genospecies and sequence types. To analyse the prevalence of Borrelia and the density of I. ricinus , confidence intervals, generalized linear mixed models, linear models, generalized linear models (Tweedie distribution), model selection (delta Akaike information criterion corrected for small sample size < 2), relative abundance index and the Shannon index were used. Results In total, 210 of the 1896 ticks collected tested positive for Borrelia (11.08%). The prevalence in I. ricinus ticks was identical in females (48/156; 30.77%) and males (44/143; 30.77%) and lower in nymphs (118/1152; 10.24%). Ixodes ricinus collected from grassland were significantly more frequently infected (29.36%) than those from woodland (6.43%). A positive correlation between land use intensity and the infection rate of ticks with B. burgdorferi s.l. was found in both grassland and woodland. Furthermore, the relative abundance index of predatory and small mammals had a positive effect on Borrelia spp. prevalence in I. ricinus nymphs. Multilocus sequence typing was performed for 184 samples. The most frequently found genospecies was Borrelia afzelii (65.76%), followed by Borrelia garinii (17.93%), Borrelia valaisiana (13.59%), and Borrelia burgdorferi sensu stricto (2.72%). Furthermore, 59 known and 41 new sequence types were detected. Conclusions Borrelia burgdorferi s.l. genotypes with zoonotic potential show variable host adaptation, which seems to promote high intraspecific pathogen diversity. The results of our study support the dilution hypothesis as they show that conserving native forests and species diversity may support the biodiversity of Borrelia spp. while reducing their overall prevalence. Graphical abstract

Background Ixodes inopinatus was described from Spain on the basis of morphology and partial sequencing of 16S ribosomal DNA. However, several studies suggested that morphological differences between I. inopinatus and Ixodes ricinus are minimal and that 16S rDNA lacks the power to distinguish the two species. Furthermore, nuclear and mitochondrial markers indicated evidence of hybridization between I. inopinatus and I. ricinus . In this study, we tested our hypothesis on tick dispersal from North Africa to Southern Europe and determined the prevalence of selected tick-borne pathogens (TBPs) in I. inopinatus , I. ricinus , and their hybrids. Methods Ticks were collected in Italy and Algeria by flagging, identified by sequencing of partial TROSPA and COI genes, and screened for Borrelia burgdorferi s.l., B. miyamotoi , Rickettsia spp. , and Anaplasma phagocytophilum by polymerase chain reaction and sequencing of specific markers. Results Out of the 380 ticks, in Italy, 92 were I. ricinus , 3 were I. inopinatus , and 136 were hybrids of the two species. All 149 ticks from Algeria were I. inopinatus . Overall, 60% of ticks were positive for at least one TBP. Borrelia burgdorferi s.l. was detected in 19.5% of ticks, and it was significantly more prevalent in Ixodes ticks from Algeria than in ticks from Italy. Prevalence of Rickettsia spotted fever group (SFG) was 51.1%, with significantly greater prevalence in ticks from Algeria than in ticks from Italy. Borrelia miyamotoi and A. phagocytophilum were detected in low prevalence (0.9% and 5.2%, respectively) and only in ticks from Italy. Conclusions This study indicates that I. inopinatus is a dominant species in Algeria, while I. ricinus and hybrids were common in Italy. The higher prevalence of B. burgdorferi s.l. and Rickettsia SFG in I. inopinatus compared with that in I. ricinus might be due to geographical and ecological differences between these two tick species. The role of I. inopinatus in the epidemiology of TBPs needs further investigation in the Mediterranean Basin. Graphical Abstract