1. The World-Wide Saga of Lyme Borreliosis

Jorge L. Benach and Juan Carlos García-Moncó

We have kept this chapter as a historical account of the early days of Lyme borreliosis in both Europe and the United States. Recent advances at all levels in this field are being updated in all the other chapters. Moreover, controversies that surround the diagnosis and treatment of this disease have been taken up in a new chapter 23 in this book. Thus, the saga of Lyme borreliosis in this chapter is told now with the same perspective as in the previous edition. The clinical-epidemiologic studies of a cluster of arthritis in Lyme, Connecticut intersected with ongoing studies on tick borne diseases in Long Island, New York to set the stage for the discovery of the spirochete agent of Lyme disease. Studies on the microbiology of spirochetes at the Rocky Mountain Laboratory in Montana were critical for the cultivation of the newly discovered organism. The multi-national clinical studies in Europe throughout the 20th century on the dermatologic and neurologic manifestations characterized and enlarged the syndrome that we now know as Lyme borreliosis. For reasons that are discussed in this chapter, controversies have arisen among advocate patient groups and the clinicians and scientists that are at the forefront of research in Lyme borreliosis. Polarized opinions on what constitutes this disease and how to treat it have resulted in unprecedented litigation involving medical societies and advocate patient groups with no obvious end in sight.

2. Multipartite Genome of Lyme Disease Borrelia: Structure, Variation and Prophages   Free download

Ira Schwartz, Gabriele Margos, Sherwood R. Casjens, Wei-Gang Qiu and Christian H. Eggers

All members of the Borrelia genus that have been examined harbour a linear chromosome that is about 900 kbp in length, as well as a plethora of both linear and circular plasmids in the 5-220 kbp size range. Genome sequences for 27 Lyme disease Borrelia isolates have been determined since the elucidation of the B. burgdorferi B31 genome sequence in 1997. The chromosomes, which carry the vast majority of the housekeeping genes, appear to be very constant in gene content and organization across all Lyme disease Borrelia species. The content of the plasmids, which carry most of the genes that encode the differentially expressed surface proteins that interact with the spirochete's arthropod and vertebrate hosts, is much more variable. Lyme disease Borrelia isolates carry between 7-21 different plasmids, ranging in size from 5-84 kbp. All strains analyzed to date harbor three plasmids, cp26, lp54 and lp17. The plasmids are unusual, as compared to most bacterial plasmids, in that they contain many paralogous sequences, a large number of pseudogenes, and, in some cases, essential genes. In addition, a number of the plasmids have features indicating that they are prophages. Numerous methods have been developed for Lyme disease Borrelia strain typing. These have proven valuable for clinical and epidemiological studies, as well as phylogenomic and population genetic analyses. Increasingly, these approaches have been displaced by whole genome sequencing techniques. Some correlations between genome content and pathogenicity have been deduced, and comparative whole genome analyses promise future progress in this arena.

3. Genomics of Relapsing Fever Spirochetes

Luke C. Kingry

The relapsing fever Borrelia are composed of a genetically diverse array of bacterial species found in many areas of the world. All species studied to date share a complex genomic structure including a long linear chromosome, an array of linear plasmids, and in some cases circular plasmids similar to the Lyme disease Borrelia. While this complex genomic structure is shared with the Lyme disease Borrelia, the relapsing fever species possess distinct genetic elements that have been shown to be important for their unique pathogenesis as compared to the Lyme disease spirochete species. Genomic characterization of relapsing fever Borrelia species has greatly accelerated over the last decade. This chapter aims to discuss those advances and the role genomics will play in the understanding of this expanding group of bacterial species.

4. Replication of the Borrelia burgdorferi Genome

Kerri Kobryn

Borrelia species possess unusual genomes that harbor multiple circular and linear replicons. The termini of the linear replicons are covalently closed DNA hairpins, structures referred to as hairpin (hp) telomeres. Hairpin telomeres are formed from replicated intermediates by a specialized DNA cleavage and rejoining reaction called telomere resolution. Current knowledge of the mechanisms of the DNA replication, hairpin telomere metabolism and replicon maintenance of these unusual, segmented genomes will be reviewed. We will also discuss proposals on how hairpin telomere metabolism may contribute to rearrangements within the linear component of the genome.

5. Gene Regulation and Transcriptomics   Free download

D. Scott Samuels, Meghan C. Lybecker, X. Frank Yang, Zhiming Ouyang, Travis J. Bourret, William K. Boyle, Brian Stevenson, Dan Drecktrah and Melissa J. Caimano

Borrelia (Borreliella) burgdorferi, along with closely related species, is the etiologic agent of Lyme disease. The spirochete subsists in an enzootic cycle that encompasses acquisition from a vertebrate host to a tick vector and transmission from a tick vector to a vertebrate host. To adapt to its environment and persist in each phase of its enzootic cycle, B. burgdorferi wields three systems to regulate the expression of genes: the RpoN-RpoS alternative sigma (σ) factor cascade, the Hk1/Rrp1 two-component system and its product c-di-GMP, and the stringent response mediated by RelBbu and DksA. These regulatory systems respond to enzootic phase-specific signals and are controlled or fine-tuned by transcription factors, including BosR and BadR, as well as small RNAs, including DsrA_Bb and Bb6S RNA. In addition, several other DNA-binding and RNA-binding proteins have been identified, although their functions have not all been defined. Global changes in gene expression revealed by high-throughput transcriptomic studies have elucidated various regulons, albeit technical obstacles have mostly limited this experimental approach to cultivated spirochetes. Regardless, we know that the spirochete, which carries a relatively small genome, regulates the expression of a considerable number of genes required for the transitions between the tick vector and the vertebrate host as well as the adaptation to each.

6. Metabolism and Physiology of Borrelia

Frank C. Gherardini, Daniel P. Dulebohn, Travis J. Bourret and Crystal L. Richards

In this chapter, we define key biochemical pathways and metabolic systems that are the underpinning of the physiology of Borrelia. Energy extracted from the fermentation of a few simple sugars fuels these biochemical reactions and also energizes a V-type ATPase (V-ATPase), establishing a membrane potential that drives motility and the transport of most solutes. After transport, metabolites and biochemical intermediates, such as simple sugars, fatty acids, purines and pyrimidines, peptides and metal ions, are chemically utilized and/or modified to provide an intracellular pool of compounds necessary for protein, nucleic acid, membrane and cell wall biosynthesis. The extremely limited de novo biosynthetic capacity of Borrelia restricts members of this genus to a host-dependent lifestyle but conserves energy and reflects a reduction of the genome that is an interesting example of adaptive biology. It is fascinating how well the metabolism and physiology of Borrelia spp. dovetail with the physiology of their vertebrate and arthropod hosts.

7. Structure, Function, Biogenesis and Maintenance of the Borrelia Cell Envelope   Free download

Wolfram R. Zückert, Brandon L. Jutras, Alvaro M. Toledo and Sven Bergström

Although Borrelia spirochaetes are often, but mistakenly, described as Gram-negative bacteria due to their diderm, i.e. double-membrane envelopes, a closer examination reveals significant differences in composition and architecture. Particularly striking is the lack of classical endotoxin/lipopolysaccharide. Instead, glycolipids and surface lipoproteins dominate the the host-pathogen interface, where they play important roles during transmission, persistence and ensuing pathogenic processes. A modified peptidoglycan cell wall is also emerging as a potent pathogenicity determinant, in addition to contributing to cell shape in concert with periplasmic flagella. While surface lipoproteins such as the Osps interact with a variety of ligands in different organ tissues, they are also targets of the immune response and several have emerged as vaccine candidates. Some of the identified periplasmic lipoproteins, i.e., the OppAs, are components of substrate transport complexes. Investigations into integral membrane proteins led to the identification of several Borrelia porins: P13, whose structure and function is unknown, DipA, which is specific for dicarboxylates, and P66, which has a dual role as a pore-forming outer membrane protein and adhesin. Tol homologs BesA, -B, and -C appear to form a Type I 'channel' to export exogenous toxic agents such as antibiotics and maintain infectivity by an unknown mechanism. Initial studies on envelope biogenesis pathways and mechanisms based on diderm proteobacterial model organisms have revealed significant deviations from the Gram-negative norm, further bolstering the unique status of Borrelia among microbial pathogens.

8. Dancing with the Star: Borrelia burgdorferi, a Solo Dancer with All the Right Moves

Ching Wooen Sze, Hui Xu, Md A. Motaleb, Charles W. Wolgemuth, Jun Liu, Nyles W. Charon and Chunhao Li

Spirochetes are unique in many features, from the physical morphology down to the molecular mechanism used for gene regulation. As the model organism discussed in this chapter, the Lyme disease bacterium Borrelia burgdorferi shows us how spirochetes do it differently when it comes to the placement of flagella, coordination of two PF bundles during motility, a spirochete-specific flagellar collar protein in the basal body/motor complex, and the absolute reliance on motility and chemotaxis for disease transmission and colonization. Motility and chemotaxis are one of the most common traits adapted by different bacterial species, yet the 'classical' paradigms of hierarchical transcriptional regulation of flagellar genes and coordination of motility and chemotaxis derived from study of model bacteria do not fit in the world of spirochetes. As the genetic and molecular tool advances in the field of B. burgdorferi, the significance of more motility and chemotaxis genes begin to unravel making it possible to establish a working model best suited for spirochetes.

9. Evolutionary Genetics of Borrelia   Free download

Zachary J. Oppler, Kayleigh R. O'Keeffe, Karen D. McCoy and Dustin Brisson

The genus Borrelia consists of evolutionarily and genetically diverse bacterial species that cause a variety of diseases in humans and domestic animals. These vector-borne spirochetes can be classified into two major evolutionary groups, the Lyme borreliosis clade and the relapsing fever clade, both of which have complex transmission cycles during which they interact with multiple host species and arthropod vectors. Molecular, ecological, and evolutionary studies have each provided significant contributions towards our understanding of the natural history, biology and evolutionary genetics of Borrelia species; however, integration of these studies is required to identify the evolutionary causes and consequences of the genetic variation within and among Borrelia species. For example, molecular and genetic studies have identified the adaptations that maximize fitness components throughout the Borrelia lifecycle and enhance transmission efficacy but provide limited insights into the evolutionary pressures that have produced them. Ecological studies can identify interactions between Borrelia species and the vertebrate hosts and arthropod vectors they encounter and the resulting impact on the geographic distribution and abundance of spirochetes but not the genetic or molecular basis underlying these interactions. In this chapter we discuss recent findings on the evolutionary genetics from both of the evolutionarily distinct clades of Borrelia species. We focus on connecting molecular interactions to the ecological processes that have driven the evolution and diversification of Borrelia species in order to understand the current distribution of genetic and molecular variation within and between Borrelia species.

10. Perpetuation of Borreliae   Free download

Sam R. Telford III and Heidi K. Goethert

With one exception (epidemic relapsing fever), borreliae are obligately maintained in nature by ticks. Although some Borrelia spp. may be vertically transmitted to subsequent generations of ticks, most require amplification by a vertebrate host because inheritance is not stable. Enzootic cycles of borreliae have been found globally; those receiving the most attention from researchers are those whose vectors have some degree of anthropophily and, thus, cause zoonoses such as Lyme disease or relapsing fever. To some extent, our views on the synecology of the borreliae has been dominated by an applied focus, viz., analyses that seek to understand the elements of human risk for borreliosis. But, the elements of borrelial perpetuation do not necessarily bear upon risk, nor do our concepts of risk provide the best structure for analyzing perpetuation. We identify the major global themes for the perpetuation of borreliae, and summarize local variations on those themes, focusing on key literature to outline the factors that serve as the basis for the distribution and abundance of borreliae.

11. Interactions Between Ticks and Lyme Disease Spirochetes   Free download

Utpal Pal, Chrysoula Kitsou, Dan Drecktrah, Özlem Büyüktanir Yaş and Erol Fikrig

Borrelia burgdorferi sensu lato causes Lyme borreliosis in a variety of animals and humans. These atypical bacterial pathogens are maintained in a complex enzootic life cycle that primarily involves a vertebrate host and Ixodes spp. ticks. In the Northeastern United States, I. scapularis is the main vector, while wild rodents serve as the mammalian reservoir host. As B. burgdorferi is transmitted only by I. scapularis and closely related ticks, the spirochete-tick interactions are thought to be highly specific. Various borrelial and arthropod proteins that directly or indirectly contribute to the natural cycle of B. burgdorferi infection have been identified. Discrete molecular interactions between spirochetes and tick components also have been discovered, which often play critical roles in pathogen persistence and transmission by the arthropod vector. This chapter will focus on the past discoveries and future challenges that are relevant to our understanding of the molecular interactions between B. burgdorferi and Ixodes ticks. This information will not only impact scientific advancements in the research of tick-transmitted infections but will also contribute to the development of novel preventive measures that interfere with the B. burgdorferi life cycle.

12. Biology and Molecular Biology of Ixodes scapularis   Free download

Daniel E. Sonenshine and Ladislav Šimo

This chapter describes the biology of the tick Ixodes scapularis in relation to its role as the vector of the Lyme disease agent, Borrelia burgdorferi. Following a review of the internal anatomy of the tick, we review basic molecular processes that contribute to an understanding of the dynamics of the tick's specialized parasitic processes, including attachment behavior, salivation; silencing of host anti-inflammatory responses to enable blood ingestion at the dermal feeding site; hemoglobin digestion and reproduction. The chapter is divided into three parts: 1) systematic and anatomical characteristics of ticks; 2) host finding, attachment, salivary disruption of host defenses, blood feeding and digestion; and 3) molecular regulation of tick bodily functions and reproduction. In the first part, we review the systematics of ticks and the taxonomic position of the vector of Lyme disease, I. scapularis, compared to other tick species. Next, we review the general organization of the tick body, including (a) the mouthparts essential for sucking blood, (b) the powerful sucking pharynx, (c) the midgut and its role in blood and hemoglobin digestion, (d) the salivary glands and their complex cellular organization, (e) the synganglion (a fused central nervous system) responsible for controlling all body functions, (f) the reproductive organs, and (g) the tracheal system that facilitates air intake and removal of CO₂. In the second part, we highlight the role of the tick's salivary glands in secreting a remarkably complex array of anti-hemostatic molecules that modulate the bite site in the host skin and how these salivary molecules facilitate the lengthy blood-sucking process. We also describe how ticks capture hemoglobin and internalize it in midgut epithelial cells for intracellular digestion, followed by the sequestration of heme into specialized hemosomes for disposal as hematin. We also will review the neural control of regulation of tick salivary glands, blood uptake, hemoglobin digestion, blood meal concentration, water/salt elimination, vitellogenesis and receptor mediated vitellogenin uptake in the developing oocytes and their oviposition.

13. Lyme Disease Pathogenesis   Free download

Jenifer Coburn, Brandon Garcia, Linden T. Hu, Mollie W. Jewett, Peter Kraiczy, Steven J. Norris and Jon Skare

Lyme disease Borrelia are obligately parasitic, tick-transmitted, invasive, persistent bacterial pathogens that cause disease in humans and non-reservoir vertebrates primarily through the induction of inflammation. During transmission from the infected tick, the bacteria undergo significant changes in gene expression, resulting in adaptation to the mammalian environment. The organisms multiply and spread locally and induce inflammatory responses that, in humans, result in clinical signs and symptoms. Borrelia virulence involves a multiplicity of mechanisms for dissemination and colonization of multiple tissues and evasion of host immune responses. Most of the tissue damage, which is seen in non-reservoir hosts, appears to result from host inflammatory reactions, despite the low numbers of bacteria in affected sites. This host response to the Lyme disease Borrelia can cause neurologic, cardiovascular, arthritic, and dermatologic manifestations during the disseminated and persistent stages of infection. The mechanisms by which a paucity of organisms (in comparison to many other infectious diseases) can cause varied and in some cases profound inflammation and symptoms remains mysterious but are the subjects of diverse ongoing investigations. In this chapter, we provide an overview of virulence mechanisms and determinants for which roles have been demonstrated in vivo, primarily in mouse models of infection.

14. Pathogenesis of Relapsing Fever   Free download

Job Lopez, Joppe W. Hovius and Sven Bergström

Relapsing fever (RF) is caused by several species of Borrelia; all, except two species, are transmitted to humans by soft (argasid) ticks. The species B. recurrentis is transmitted from one human to another by the body louse, while B. miyamotoi is vectored by hard-bodied ixodid tick species. RF Borrelia have several pathogenic features that facilitate invasion and dissemination in the infected host. In this chapter, we discuss the dynamics of vector acquisition and subsequent transmission of RF Borrelia to their vertebrate hosts. We also review taxonomic challenges for RF Borrelia as new species have been isolated throughout the globe. Moreover, aspects of pathogenesis including symptomology, neurotropism, erythrocyte and platelet adhesion are discussed. We expound on RF Borrelia evasion strategies for innate and adaptive immunity, focusing on the most fundamental pathogenetic attributes, multiphasic antigenic variation. Lastly, we review new and emerging species of RF Borrelia and discuss future directions for this global disease.

15. Animal Models of Borreliosis

Monica E. Embers, Stephen W. Barthold and Diego Cadavid

Animal models have been extremely useful for understanding many features of infection with Borrelia species, including pathogenesis, host responses, host-vector interactions, in vivo bacterial gene expression, vaccine responses, and chemotherapy. In particular, the smaller animal models have been beneficial in understanding the molecular pathogenesis of Lyme and relapsing fever spirochetes, mechanisms of immune evasion and generation of arthritis. The larger animal models including dogs and primates, have been valuable for the development of vaccines and diagnostics. Each animal model brings its own set of benefits for studying aspects of borreliosis, which is what we aim to convey in this chapter. We begin with the laboratory mouse, with which the majority of borreliosis studies have been conducted. We also discuss wild mice and other rodent models, rabbits, dogs, horses and nonhuman primates. We conclude with a summary of results in animal models on the controversial topic of antimicrobial efficacy. Some degree of overlap may exist with these subjects that are covered in other chapters, but the goal of this chapter is to focus on the practical aspects of various animal models used for Lyme borreliosis and relapsing fever research.

16. Genetic Manipulation of Borrelia   Free download

Patricia A. Rosa and Mollie W. Jewett

Genetic studies in Borrelia require special consideration of the highly segmented genome, complex growth requirements and evolutionary distance of spirochetes from other genetically tractable bacteria. Despite these challenges, a robust molecular genetic toolbox has been constructed to investigate the biology and pathogenic potential of these important human pathogens. In this chapter we summarize the tools and techniques that are currently available for the genetic manipulation of Borrelia, including the relapsing fever spirochetes, viewing them in the context of their utility and shortcomings. Our primary objective is to help researchers discern what is feasible and what is not practical when thinking about potential genetic experiments in Borrelia. We have summarized published methods and highlighted their critical elements, but we are not providing detailed protocols. Although many advances have been made since B. burgdorferi was first transformed over 25 years ago, some standard genetic tools remain elusive for Borrelia. We mention these limitations and why they persist, if known. We hope to encourage investigators to explore what might be possible, in addition to optimizing what currently can be achieved, through genetic manipulation of Borrelia.

17. Live Imaging   Free download

George Chaconas, Tara J. Moriarty, Jon Skare and Jenny A. Hyde

Being able to vizualize a pathogen at a site of interaction with a host is an aesthetically appealing idea and the resulting images can be both informative as well as enjoyable to view. Moreover, the approaches used to derive these images can be powerful in terms of offering data unobtainable by other methods. In this chapter, we review three primary modalities for live imaging Borrelia spirochetes: whole animal imaging, intravital microscopy and live cell imaging. Each method has strengths and weaknesses, which we review, as well as specific purposes for which they are optimally utilized. Live imaging borriliae is a relatively recent development and the first edition of this book lacked a chapter to cover the area, which was in its infancy. Here, in addition to the methods themselves, we also review areas of spirochete biology that have been significantly impacted by live imaging and present a collection of images associated with the forward motion in the field driven by imaging studies.

18. Immune Response to Borrelia: Lessons from Lyme Disease Spirochetes   Free download

Linda K. Bockenstedt, R. Mark Wooten and Nicole Baumgarth

The mammalian host responds to infection with Borrelia spirochetes through a highly orchestrated immune defense involving innate and adaptive effector functions aimed toward limiting pathogen burdens, minimizing tissue injury, and preventing subsequent reinfection. The evolutionary adaptation of Borrelia spirochetes to their reservoir mammalian hosts may allow for its persistence despite this immune defense. This review summarizes our current understanding of the host immune response to B. burgdorferi sensu lato, the most widely studied Borrelia spp. and etiologic agent of Lyme borreliosis. Pertinent literature will be reviewed with emphasis on in vitro, ex vivo and animal studies that influenced our understanding of both the earliest responses to B. burgdorferi as it enters the mammalian host and those that evolve as spirochetes disseminate and establish infection in multiple tissues. Our focus is on the immune response of inbred mice, the most commonly studied animal model of B. burgdorferi infection and surrogate for one of this pathogen's principle natural reservoir hosts, the white-footed deer mouse. Comparison will be made to the immune responses of humans with Lyme borreliosis. Our goal is to provide an understanding of the dynamics of the mammalian immune response during infection with B. burgdorferi and its relation to the outcomes in reservoir (mouse) and non-reservoir (human) hosts.

19. Human and Veterinary Vaccines for Lyme Disease   Free download

Nathaniel S. O'Bier, Amanda L. Hatke, Andrew C. Camire and Richard T. Marconi

Lyme disease (LD) is an emerging zoonotic infection that is increasing in incidence in North America, Europe, and Asia. With the development of safe and efficacious vaccines, LD can potentially be prevented. Vaccination offers a cost-effective and safe approach for decreasing the risk of infection. While LD vaccines have been widely used in veterinary medicine, they are not available as a preventive tool for humans. Central to the development of effective vaccines is an understanding of the enzootic cycle of LD, differential gene expression of Borrelia burgdorferiin response to environmental variables, and the genetic and antigenic diversity of the unique bacteria that cause this debilitating disease. Here we review these areas as they pertain to past and present efforts to develop human, veterinary, and reservoir targeting LD vaccines. In addition, we offer a brief overview of additional preventative measures that should employed in conjunction with vaccination.

20. Lyme Borreliosis in Domestic Animals

Stephen W. Barthold

Several domestic animals, including dogs, cats, horses, cows and small ruminants are frequent incidental hosts for infection with Borrelia burgdorferi sensu lato (s.l.). Subclinical infection is quite common, but all species covered in this chapter may develop clinical disease. Disease manifestations are variable and often transient, but arthritis is common. Neuroborreliosis has been described in dogs and is a particularly noteworthy syndrome in horses. The dog has served as an experimental model, and considerable information on B. burgdorferi pathogenesis, therapy and prevention is available for this species.

21. Epidemiology of Lyme Disease

Paul Mead and Amy Schwartz

Lyme disease affects populations throughout the northern hemisphere, with regional patterns reflecting differences in pathogen genospecies, vector biology, and human behavior. In the United States, reported cases increased from ~9,000 in 1992 to nearly 34,000 in 2018. The number of patients treated for Lyme disease is estimated at 300,000 annually. U.S. cases are focused in the Northeast and upper Midwest regions; however, these foci are expanding. Lyme disease cases have a distinct bimodal distribution relative to age, peaking among children aged 5 to 15 years and adults aged 60 years or older. Clinical features are influenced by both pathogen and host factors. A firm understanding of Lyme disease epidemiology is important for clinician and researcher alike.

22. Lyme Disease Diagnostics

Michael R. Mosel, John Aucott, Steve E. Schutzer, Adriana Marques, Paul M. Arnaboldi, Raymond Dattwyler and Mark W. Eshoo

Lyme disease, which is caused by Borrelia burgdorferi sensu lato infection from a tick bite, is growing with more than 300,000 estimated cases each year in the US alone. If diagnosed and treated early, antibiotics are most effective at eradicating infection and preventing sequelae. However, early diagnosis can be challenging in many instances. This chapter describes challenges regarding the clinical diagnosis of early Lyme disease and focuses on the current and future methodologies for detecting the presence of B. burgdorferi in clinical specimens. Both direct and indirect methods for pathogen detection are presented with regard to early and later-stage Lyme disease. In addition, potential alternative and evolving diagnostic methods such as detection of human host response and xenodiagnosis are discussed.

23. The Widening Gyre: Controversies in Lyme Disease

Adriana Marques, Jacob E. Lemieux and Linden T. Hu

In this chapter we explore controversies surrounding the issues of chronic Lyme disease (CLD) and post-treatment Lyme disease (PTLD) syndrome. We describe each of the terms as they are used in the literature and then will look at the data supporting (or not supporting) some of the most prominent hypotheses for their etiology. Among the areas we will discuss are roles in PTLD for autoimmunity, immune dysregulation or maladaptive host responses, the persistence of bacterial remnants that cause chronic immune stimulation; and chronic infection by Borrelia burgdorferi. Our examination of the data shows that there still remains much to be known about CLD and PTLD, and we provide recommendations for future research to try to resolve the controversies.

24. Lyme Disease in Humans   Free download

Justin D. Radolf, Klemen Strle, Jacob E. Lemieux and Franc Strle

Lyme disease (Lyme borreliosis) is a tick-borne, zoonosis of adults and children caused by genospecies of the Borrelia burgdorferi sensu lato complex. The ailment, widespread throughout the Northern Hemisphere, continues to increase globally due to multiple environmental factors, coupled with increased incursion of humans into habitats that harbor the spirochete. B. burgdorferi sensu lato is transmitted by ticks from the Ixodes ricinus complex. In North America, B. burgdorferi causes nearly all infections; in Europe, B. afzelii and B. garinii are most associated with human disease. The spirochete's unusual fragmented genome encodes a plethora of differentially expressed outer surface lipoproteins that play a seminal role in the bacterium's ability to sustain itself within its enzootic cycle and cause disease when transmitted to its incidental human host. Tissue damage and symptomatology (i.e., clinical manifestations) result from the inflammatory response elicited by the bacterium and its constituents. The deposition of spirochetes into human dermal tissue generates a local inflammatory response that manifests as erythema migrans (EM), the hallmark skin lesion. If treated appropriately and early, the prognosis is excellent. However, in untreated patients, the disease may present with a wide range of clinical manifestations, most commonly involving the central nervous system, joints, or heart. A small percentage (~10%) of patients may go on to develop a poorly defined fibromyalgia-like illness, post-treatment Lyme disease (PTLD) unresponsive to prolonged antimicrobial therapy. Below we integrate current knowledge regarding the ecologic, epidemiologic, microbiologic, and immunologic facets of Lyme disease into a conceptual framework that sheds light on the disorder that healthcare providers encounter.