Materiały źródłowe

• #1 Lyme Disease Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8046170/

  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. […] 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.

• #2 Lyme Disease Pathogenesis – PubMed

  https://pubmed.ncbi.nlm.nih.gov/33353871/

  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. […] 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.

• #3 Lyme Disease Pathogenesis

  https://www.mdpi.com/1467-3045/42/1/15

  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. […] 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.

• #4 Lyme disease – Wikipedia

  https://en.wikipedia.org/wiki/Lyme_disease

  B. burgdorferi can spread throughout the body during the course of the disease, and has been found in the skin, heart, joints, peripheral nervous system, and central nervous system. […] B. burgdorferi does not produce toxins. Therefore, many of the signs and symptoms of Lyme disease are a consequence of the immune response to spirochete in those tissues. […] B. burgdorferi is injected into the skin by the bite of an infected Ixodes tick. Tick saliva, which accompanies the spirochete into the skin during the feeding process, contains substances that disrupt the immune response at the site of the bite. This provides a protective environment where the spirochete can establish infection. The spirochetes multiply and migrate outward within the dermis. The host inflammatory response to the bacteria in the skin causes the characteristic circular EM lesion.

• #5 Faculty Collaboration Database – Lyme Disease Pathogenesis. Curr Issues Mol Biol 2021;42:473-518

  https://fcd.mcw.edu/?search/showPublication/id/1488144

  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. […] 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.

• #6 Lyme Disease – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/spirochetes/lyme-disease

  B. burgdorferi enters the skin at the site of the tick bite. After 3 to 32 days, the organisms migrate locally in the skin around the bite, spread via the lymphatics to cause regional adenopathy or disseminate in blood to organs or other skin sites. Initially, an inflammatory reaction (erythema migrans) occurs before significant antibody response to infection (serologic conversion). […] Erythema migrans, the hallmark and best clinical indicator of Lyme disease, is the first sign of the disease. It occurs in at least 75% of patients, beginning as a red or dark macule or papule at the site of the tick bite, usually on the proximal portion of an extremity or the trunk (especially the thigh, buttock, or axilla), between 3 days and 32 days after a tick bite. […] Symptoms of early-disseminated disease begin days or weeks after the appearance of the primary lesion, when the bacteria spread through the body.

• #7 Lyme disease – Wikipedia

  https://en.wikipedia.org/wiki/Lyme_disease

  Neutrophils, however, which are necessary to eliminate the spirochetes from the skin, fail to appear in necessary numbers in the developing EM lesion because tick saliva inhibits neutrophil function. This allows the bacteria to survive and eventually spread throughout the body. […] Days to weeks following the tick bite, the spirochetes spread via the bloodstream to joints, heart, nervous system, and distant skin sites, where their presence gives rise to the variety of symptoms of the disseminated disease. The spread of B. burgdorferi is aided by the attachment of the host protease plasmin to the surface of the spirochete. […] If untreated, the bacteria may persist in the body for months or even years, despite the production of B. burgdorferi antibodies by the immune system. The spirochetes may avoid the immune response by decreasing expression of surface proteins that are targeted by antibodies, antigenic variation of the VlsE surface protein, inactivating key immune components such as complement, and hiding in the extracellular matrix, which may interfere with the function of immune factors.

• #8 Lyme Disease: Practice Essentials, Background, Etiology

  https://emedicine.medscape.com/article/330178-overview

  Once the spirochete is in the skin, one of three events may occur: […] The spirochete may remain viable and localized in the skin, where it produces erythema migrans (EM), the characteristic skin lesion of Lyme disease. […] After entering the circulation, the organism shows a distinct tropism for the skin, heart, central nervous system (CNS), joints, and eyes. […] The clinical manifestations of Lyme disease generally follow three stages of disease progression: early localized, early disseminated, and chronic disseminated. […] The infection progresses to disseminated disease in approximately 50% of untreated patients. […] The spirochete may be overwhelmed and eliminated by host defense mechanisms. […] Within days to weeks, the spirochete may disseminate through the lymphatics or blood.

• #9 Lyme Disease Pathogenesis and Clinical Findings | Calgary Guide

  https://calgaryguide.ucalgary.ca/lyme-disease-pathogenesis-and-clinical-findings/lyme-disease/

  Lyme Disease: Pathogenesis and clinical findings […] Binding of OspC (a surface protein expressed by B. Burgdorferi) to human plasminogen allowing the spirochete to spread from bite site to other host organs and tissues […] B. burgdorferi spreads through skin and other tissues via bloodstream in human host. […] Ongoing and repeated innate and adaptive host immune response to B. burgdorferi Chronic inflammatory state results in synovial hypertrophy, vascular proliferation, and mononuclear cell infiltrate in large joints […] Systemic inflammatory response after dissemination of the spirochete to body tissues and organs.

• #10 Lyme Disease and Relapsing Fever Spirochetes: Genomics, Molecular Biology, Host Interactions and Disease Pathogenesis

  https://www.caister.com/lyme

  Lyme disease (Lyme borreliosis) is the most prevalent vector-borne illness in the United States and Europe and a growing threat to global health. […] This current volume, by the same editors, builds on the previous work and contains a vast amount of new information, a wider scope, and increased coverage of genomics, genetics, evolutionary biology, vector biology, physiology, pathogenicity, immune response, and immune evasion. […] The volume highlights and describes in detail the tremendous advances in understanding of the Borrelia genus at the molecular and cellular levels as well as the pathogenesis of Lyme disease and relapsing fever. […] 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.

• #11 Lyme Disease Pathogenesis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8046170/

  Immune responses, both innate and adaptive contribute to control of the numbers of the organisms but also contribute to tissue pathology and disease manifestations. […] Emerging themes regarding the pathogenesis of Lyme disease include (i) B. burgdorferi encodes several multi-function proteins, (ii) B. burgdorferi encodes several distinct proteins that may inhibit host complement activity at different stages of the cascade, (iii) immune responses to B. burgdorferi are not only responsible for controlling bacterial numbers, but also for disease manifestations, and (iv) B. burgdorferi encodes multiple adhesins that play distinct roles in the infection process.

• #12

  https://www.jci.org/articles/view/21681

  Since its identification nearly 30 years ago, Lyme disease has continued to spread, and there have been increasing numbers of cases in the northeastern and north central US. The Lyme disease agent, Borrelia burgdorferi, causes infection by migration through tissues, adhesion to host cells, and evasion of immune clearance. Both innate and adaptive immune responses, especially macrophage- and antibody-mediated killing, are required for optimal control of the infection and spirochetal eradication. […] The most remarkable aspect of the B. burgdorferi genome is the large number of sequences encoding predicted or known lipoproteins, including outer-surface proteins (Osps) A through F. […] Instead, this extracellular pathogen causes infection by migration through tissues, adhesion to host cells, and evasion of immune clearance.

• #13 How Lyme Disease Bacteria Migrate Through Blood Vessels

  https://www.contagionlive.com/view/how-lyme-disease-bacteria-migrate-through-blood-vessels

  A recent study has shown that Borrelia burgdorferi, the bacterium that causes Lyme disease, spreads throughout the body by crawling along the inside wall—the endothelium—of blood vessels. […] The findings of this study have provided insight into physical mechanisms of bacterial-endothelial interactions, and revealed remarkable similarities in the mechanisms by which bacteria and leukocytes interact with and move over endothelial surfaces, including dependence on tethers and catch bonds, the authors write. […] Bacteria circulating in the bloodstream face the same mechanical barriers to vascular adhesion and extravasation as circulating host cells, but the physical mechanisms permitting their adhesion to vascular surfaces under physiological shear stress are largely unknown, the authors add.

• #14 Something to Grapple with: How Wily Lyme Disease Prowls the Body | Scientific American

  https://www.scientificamerican.com/article/something-to-grapple-with-how-wily-lyme-disease-prowls-the-body/

  Lyme disease is an incredibly evasive adversary. No one is entirely sure how the bacterium that causes it spreads so widely throughout the body or why symptoms sometimes persist after the infection has been treated with antibiotics. Now researchers at the University of Toronto may finally have an explanation: The tiny, spiral-shaped bacterium called Borrelia burgdorferi can quickly grapple along the inner surfaces of blood vessels to get to vulnerable tissues or to hiding places where it can hole up beyond the reach of drugs. […] B. burgdorferi uses a special adhesive protein on its surface to grab like a hook onto the endothelial cells that line blood vessels, attaching and detaching rapidly as it migrates to its destination, the Toronto microbiologists explain in a new study published Thursday in Cell Reports. This mechanism is how the bacteria can overcome the fast flow of blood and avoid getting swept away, says lead author Rhodaba Ebady. It is also likely that this tactic helps the pathogens get to sites where they are able to evade the immune system and treatment, Ebady says.

• #15 Nanomechanical mechanisms of Lyme disease spirochete motility enhancement in extracellular matrix | Communications Biology

  https://www.nature.com/articles/s42003-021-01783-1

  The goal here was to pursue the assumption that adhesins not only provide stationary attachments alone but also temporarily enhance the movement of the spirochetes. […] The standard methods that are used in studying the specific gene effects on borrelial motility are solely in vitro studies, lacking the vast majority of components and environmental signals which the spirochete faces during its infectious cycle. […] Together, these data show that the enhancement of borrelial motility is caused by certain DbpAB-ECM interactions. […] Our results reveal that a possible strategy how spirochetes coordinate the transition between these motility states, is by forming various bonds of different mechanical properties that are tuned by external forces. […] The increased stability of DbpA/decorin when force-loaded is tailored for spirochetes to withstand shear stress, thereby facilitating dissemination within vascular endothelia in blood vessels.

• #16 Nanomechanical mechanisms of Lyme disease spirochete motility enhancement in extracellular matrix | Communications Biology

  https://www.nature.com/articles/s42003-021-01783-1

  Although certain binding interactions might prevail at a certain motility state, the differing kinetics between the DbpA/B proteins and the various components of the ECM need to work together synchronously as a single strategy to enhance motility through the ECM. […] We show that DbpA/B are multifunctional proteins, which through binding either directly to ECM proteins or their associated glycosaminoglycans side chains, are capable to propel and coordinate the movement within the ECM. […] Together, these interactions help spirochetes to reach extraordinary high speeds, which enable them to colonize a host and to avoid clearance by the immune system of a host more efficiently. […] In summary, we showed that spirochetes, despite a limited number of adhesive molecules, are able to leverage a wide variety of adhesion strategies in order to streamline their dissemination through the host.

• #17 The Brilliance of Borrelia: Mechanisms of Host Immune Evasion by Lyme Disease-Causing Spirochetes

  https://www.mdpi.com/2076-0817/10/3/281

  Lyme disease (LD) has become the most common vector-borne illness in the northern hemisphere. The causative agent, Borrelia burgdorferi sensu lato, is capable of establishing a persistent infection within the host. This is despite the activation of both the innate and adaptive immune responses. B. burgdorferi utilizes several immune evasion tactics ranging from the regulation of surface proteins, tick saliva, antimicrobial peptide resistance, and the disabling of the germinal center. This review aims to cover the various methods by which B. burgdorferi evades detection and destruction by the host immune response, examining both the innate and adaptive responses. By understanding the methods employed by B. burgdorferi to evade the host immune response, we gain a deeper knowledge of B. burgdorferi pathogenesis and Lyme disease, and gain insight into how to create novel, effective treatments.

• #18 Immunopathogenesis of Lyme disease – UpToDate

  https://www.uptodate.com/contents/immunopathogenesis-of-lyme-disease

  Advances in the understanding of the interactions that occur between Borrelia burgdorferi and its mammalian and tick hosts have led to important insights into the pathogenic mechanisms that underlie the manifestations of human Lyme disease. […] The lifecycle of B. burgdorferi requires that it survive in two distinct environments — that found in a tick host and that found in a mammalian host. […] The ability of B. burgdorferi to cause long-term infection in its tick and mammalian hosts requires that it implement strategies to successfully evade and subvert host immune defenses. […] In this topic, we will describe some of the mechanisms that B. burgdorferi uses to establish infection as well as the host immune responses to invasion by the organism that both help control the infection and also cause some of the manifestations of Lyme disease. […] Outer surface protein variations — B. burgdorferi exit the tick while it feeds on a mammalian host and establish infection in the skin.

• #19 The Brilliance of Borrelia: Mechanisms of Host Immune Evasion by Lyme Disease-Causing Spirochetes

  https://www.mdpi.com/2076-0817/10/3/281

  For B. burgdorferi to persist in the host, the pathogen must employ a variety of tactics to evade the immune response. This review aims to provide a current overview of a majority of the immune evasion tactics employed by B. burgdorferi. […] B. burgdorferi evades the complement system in two main methods. The first method involves a direct inference with the components of the complement cascade pathways. Direct interference is accomplished through the use of outer surface proteins, the most notable of which include BBK32, OspA, OspC, and BBA70. […] The enzyme plasmin is a known inhibitor of the complement system due to its binding and cleaving of Cb3 and C5. […] The outer surface protein OspA has been shown to bind plasminogen; however, its expression is downregulated once the spirochete enters the vertebrate host. OspC, another outer surface protein found in Lyme spirochetes, has been shown to bind to plasminogen and its expression is upregulated in the vertebrate host.

• #20 The Brilliance of Borrelia: Mechanisms of Host Immune Evasion by Lyme Disease-Causing Spirochetes

  https://www.mdpi.com/2076-0817/10/3/281

  The complement-regulator acquiring surface protein (CRASP) CspA has also been shown to bind plasminogen. […] The expression of CspA is upregulated during the tick blood meal, but downregulated in the vertebrate host, indicating that it is important in avoiding the immune response during transmission, but is not essential for continued infection. […] The proteins found in tick saliva have been shown to inhibit the complement system. The tick salivary protein, Salp15, binds to OspC both in vitro and in vivo to protect Lyme spirochetes from antibody-mediated killing. […] Salp15 from I. persulcatus is capable of binding to OspC to protect spirochetes from antibody-mediated killing and phagocytosis. […] The infection of I. scapularis nymphs with B. burgdorferi s.s. resulted in a higher expression level of TSLPI mRNA after 24 h of tick attachment compared to uninfected ticks.

• #21 The Brilliance of Borrelia: Mechanisms of Host Immune Evasion by Lyme Disease-Causing Spirochetes

  https://www.mdpi.com/2076-0817/10/3/281

  B. burgdorferi has demonstrated resistance to antimicrobial proteins and peptides in response to pathogens. […] The resistance to lactoferrin, an iron-binding and transport protein, is due, in part, to the fact that B. burgdorferi does not require iron. […] B. burgdorferi is also highly resistant to the antimicrobial peptide cathelicidin. […] The lipid membrane of B. burgdorferi was found to be a target of damage by ROS. […] One of the most important are enzymes known as superoxide dismutases (SODs) that are used to break down superoxides. […] B. burgdorferi is capable of hiding from the immune system in vitro by invaginating itself through binding to fibrocytic cells. […] Studies have shown that Borrelia spirochetes are capable of intracellular localization. […] The humoral response is one of the main mechanisms by which the adaptive immune response operates.

• #22 The Brilliance of Borrelia: Mechanisms of Host Immune Evasion by Lyme Disease-Causing Spirochetes

  https://www.mdpi.com/2076-0817/10/3/281

  The invasion of the lymphoid tissue disrupts the ability of the immune response to form functioning germinal centers (GC). […] B. burgdorferi also evades detection through the antigenic variation of the outer surface protein VlsE. […] Though research in recent decades has shed light on the mechanisms by which B. burgdorferi evades the immune response, there is still much to be learned. More research is needed to elucidate the exact mechanisms that B. burgdorferi uses to interact with and evade the different parts of the immune response. A better understanding of how B. burgdorferi subverts the host immune response is important to the development of novel treatments and preventative measures.

• #23 The role of dendritic cells in the pathogenesis of Lyme disease

  https://www.termedia.pl/The-role-of-dendritic-cells-in-the-pathogenesis-of-Lyme-disease,10,22042,1,1.html

  Borrelia burgdorferi is able to induce the production of several antimicrobial peptides, including human -defensin-2 and cathelicidin LL-37, in human resident skin cells (fibroblasts and keratinocytes), mast cells, macrophages, NK cells, neutrophils and DCs, fibroblasts and keratinocytes. […] Dendritic cells are the first-line defense in the skin and influence the course of the infection. […] The most important effect of the activity of ticks saliva is inhibition of T-cells proliferation and inhibition of Th1 cytokines release, such as interferon (IFN-) and interleukin 2 (IL-2). […] Salp15 interacts mainly with DC-SIGN receptor on DCs, what lead to the reduction of proinflammatory cytokines secretion (IL-12, IL-6, TNF-), essential in T lymphocytes activation in lymph nodes, and directly binds CD4 receptors of the lymphocytes inhibiting them in the area of inflammation.

• #24 The role of dendritic cells in the pathogenesis of Lyme disease

  https://www.termedia.pl/The-role-of-dendritic-cells-in-the-pathogenesis-of-Lyme-disease,10,22042,1,1.html

  Similar inhibiting properties of Salp15 were observed in the secretion of proinflammatory cytokines (IL-12p70, IL-6, TNF-) released by DCs as a response to LPS antigen. […] This inhibitor has high affinity towards cathepsin L and partial cathepsin S. […] Hence, Sialol inhibits pathogen induced DCs maturation and leads to the inhibition of antigen specific T-lymphocytes proliferation. […] Hence, local immunosuppression due to the activity of the tick facilitates transmission and the development of infection with B. burgdorferi. […] These observations revealed a complex inhibitory effect exerted by tick saliva on DCs function. […] Dendritic cells are a group of highly specialized cells transforming and presenting foreign antigens (APCs). […] Dendritic cells not only influence the type of T-cell response, but also participate in the activation and recruitment of the immature DC, NK, macrophages, granulocytes and B-lymphocytes.

• #25 Report of the Pathogenesis and Pathophysiology of Lyme Disease Subcommittee to the Tick-Borne Disease Working Group | Health.govLock

  https://www.hhs.gov/ash/advisory-committees/tickbornedisease/reports/pathogenesis-pathophysiology-lyme-disease-subcomm-2020/index.html

  Notably, mice never clear B. burgdorferi infection without antibiotic treatment; humans and nonhuman primates appear to harbor low-level, persistent B. burgdorferi infection as well. […] Persistence appears to be a function of active immune suppression and immune evasion tactics. […] Evidence now exists, from the results of experiments in both murine and nonhuman primate models, that persisting B. burgdorferi can be metabolically active, expressing certain bacterial genes and inducing gene expression changes in the infected host, despite being non-culturable following antibiotic treatment. […] These findings raise additional questions: What are the precise mechanisms by which B. burgdorferi evades, alters, or suppresses immune responses? […] What are the mechanisms by which B. burgdorferi infection causes ongoing arthritic joint disease in a subset of patients?

• #25 Report of the Pathogenesis and Pathophysiology of Lyme Disease Subcommittee to the Tick-Borne Disease Working Group | Health.govLock

  https://www.hhs.gov/ash/advisory-committees/tickbornedisease/reports/pathogenesis-pathophysiology-lyme-disease-subcomm-2020/index.html

  Are ongoing disease symptoms caused by the presence of Borrelia antigens (such as peptidoglycans) rather than active infection and, if so, why are they not cleared from the host? […] The bacteria may become antibiotic-tolerant, requiring repeated courses of antibiotic treatment or periods of treatment alternating with periods of no treatment.

• #26 Report of the Pathogenesis and Pathophysiology of Lyme Disease Subcommittee to the Tick-Borne Disease Working Group | Health.govLock

  https://www.hhs.gov/ash/advisory-committees/tickbornedisease/reports/pathogenesis-pathophysiology-lyme-disease-subcomm-2020/index.html

  To better understand the pathogenesis and pathophysiology of Lyme disease, especially in its ability to establish persistence in vertebrate species, including humans, the progression of B. burgdorferi from its reservoir in the Ixodes tick to transmission into the vertebrate host and to its localization and persistence in neural and other tissues are key steps towards eventually finding means to intervene and resolve the infection. […] B. burgdorferi can sense whether it is located in a tick or mammal and adapt its response to environmental signals, such as temperature, pH, oxygen levels, carbon dioxide levels, nutrient availability, and reactive oxygen species. […] Immunocompetent mice establish persistent and non-resolving infection. […] Data suggest that B. burgdorferi suppresses effective adaptive immunity and, therefore, that the immune system is key to understanding persistence of Lyme disease.

• #27 The bulls-eye rash of Lyme disease: Investigating the cutaneous host-pathogen dynamics of erythema migrans.

  https://asm.org/articles/2018/april/going-skin-deep-investigating-the-cutaneous-host-p

  Ixodes scapularis, commonly known as the deer tick, is the primary vector of Borrelia burgdorferi in the United States. According to the CDC, this flagellated spirochete bacterium causes approximately 30,000 cases of Lyme disease in the U.S. each year. The most recognizable symptom of early, untreated Lyme disease is erythema migrans, the bulls-eye rash. […] The key difference is the presence of the microbe. When an insect or arachnid that isnt carrying disease bites a human host, foreign components in the saliva generate an allergic response. […] But because B. burgdoferi actually causes infection of the skin, the development of erythema migrans depends not only on the innate immune response of the host, but also the pathogenic properties of the bacteria. […] Once B. burgdorferi enters the skin, the tick bite and the presence of bacteria in the dermis initiate the innate immune response of the host. Meanwhile, the spirochetes replicate locally and spread away from the point of entry at speeds of ~1-4 m per second, or a little over half of an inch per hour at maximum speeds. As a result, the bullseye rash consists of two inflammatory reactions: one to the salivary proteins that stay put, and one to the bacteria that are moving away from the site of the bite.

• #28 Lyme Disease – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/spirochetes/lyme-disease

  Other late findings (occurring years after onset) include an antibiotic-sensitive skin lesion (acrodermatitis chronica atrophicans) and chronic central nervous system abnormalities, either polyneuropathy or a subtle encephalopathy with mood, memory, and sleep disorders. […] Some patients have symptoms such as fatigue, headache, joint and muscle aches, and cognitive problems after successful antibiotic treatment. These symptoms are collectively referred to as post-treatment Lyme disease syndrome (PTLDS).

• #29 Lyme Disease – Infectious Diseases – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/infectious-diseases/spirochetes/lyme-disease

  Neurologic abnormalities develop in about 15% of patients within weeks to months of erythema migrans (generally before arthritis occurs), commonly last for months, and usually resolve completely. Most common are lymphocytic meningitis (cerebrospinal fluid [CSF] pleocytosis of about 100 cells/mcL) or meningoencephalitis, cranial neuritis (especially Bell palsy, which may be bilateral), and sensory or motor radiculoneuropathies, alone or in combination. […] Myocardial abnormalities occur in about 8% of patients within weeks of erythema migrans. They include fluctuating degrees of atrioventricular block (first-degree, Wenckebach, or third-degree) and, rarely, myopericarditis with chest pain, reduced ejection fractions, and cardiomegaly. […] In untreated Lyme disease, the late stage begins months to years after initial infection. Arthritis develops in about 60% of patients within several months, occasionally up to 2 years, of disease onset (as defined by erythema migrans). Intermittent swelling and pain in a few large joints, especially the knees, typically recur for several years.

• #30 The Lyme disease spirochete Borrelia burgdorferi induces inflammation and apoptosis in cells from dorsal root ganglia | Journal of Neuroinflammation | Full Text

  https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-10-88

  Lyme neuroborreliosis (LNB), caused by the spirochete Borrelia burgdorferi, affects both the peripheral and the central nervous systems. […] We hypothesized that Borrelia burgdorferi induces inflammatory mediators in glial and neuronal cells and that this inflammatory milieu precipitates glial and neuronal apoptosis. […] In this model, Borrelia burgdorferi induced an inflammatory response and neuronal apoptosis of DRG. These pathophysiological processes could contribute to peripheral neuropathy in LNB. […] The mechanisms underlying the pathogenesis of peripheral LNB are not clearly understood. Based on our observations, we hypothesized that Borrelia burgdorferi was able to induce inflammatory mediators in glial and neuronal cells and that this inflammatory context precipitated glial and neuronal apoptosis.

• #31 The Lyme disease spirochete Borrelia burgdorferi induces inflammation and apoptosis in cells from dorsal root ganglia | Journal of Neuroinflammation | Full Text

  https://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-10-88

  The pathogenesis of Lyme disease neuropathies is poorly understood. Borrelia burgdorferi infection may damage neural cells by the direct action of spirochetes or spirochetal products on glial and neuronal cells. […] The potential of Borrelia burgdorferi to induce cytokines, chemokines and other inflammatory mediators in glial and neuronal cells as well as glial and neuronal apoptosis has been well documented. […] We documented the ability of Borrelia burgdorferi to elicit the production of IL-6, IL-8, and CCL2 in cells of the DRG and to induce the death of sensory neurons in DRG cell cultures. […] These results support our hypothesis and show that innate responses of neuronal and glial cells of the DRG to Borrelia burgdorferi mediate inflammation and that neuronal apoptosis occurs in this context. […] We propose that inflammation of nerve roots and DRG and subsequent apoptosis in the DRG could be early events that contribute to peripheral neuropathy in Lyme neuroborreliosis.

• #32 Lyme Disease < Rheumatology, Allergy & Immunology

  https://medicine.yale.edu/internal-medicine/raci/rheumatology/research/lyme/

  Lyme disease research in the Yale Section of Rheumatology is directed toward understanding disease pathogenesis in mouse models and humans, using genomic, proteomics and state-of-the-art imaging techniques. […] The Bockenstedt laboratory studies mechanisms of host defense, including innate and adaptive immune mechanisms. […] The focus has been on the innate defense against this pathogen and use of 2-photon intravital microscopy to evaluate tick-transmitted spirochetal infection and antibiotic responsiveness in mice. […] The Lyme disease spirochete has a predilection for connective tissue, including the entheses of joints, and on-going studies are evaluating the impact of infection on tendon biology.

• #33

  https://www.jci.org/articles/view/138062

  Lyme disease, which is epidemic in certain communities, primarily in the northeastern United States, is caused by the tick-borne spirochete Borrelia burgdorferi (also called Borreliella burgdorferi). […] The basic pathogenetic feature of postinfectious LA is the development of an excessive, dysregulated proinflammatory immune response during the infection, characterized by exceptionally high IFN- levels, which persists in the postinfectious period. […] The consequences of this excessive proinflammatory response in Lyme synovia include vascular damage, autoimmune and cytotoxic processes, and fibroblast proliferation and fibrosis. […] In a transcriptomic analysis of postinfectious LA synovial tissue, a heightened IFN- signature correlated inversely with the expression of genes involved in the repair of damaged tissue.

• #34 Elucidating the role of peptidoglycan from Borrelia burgdorferi in Lyme disease pathogenesis

  https://vtechworks.lib.vt.edu/items/bb68603d-82cf-4050-a208-6e1f0dfb696c

  As of 2024, more than 50,000 people suffer from Lyme arthritis a debilitating late-stage symptom of Lyme disease. Symptoms remain even after the completion of antibiotic therapy and when there is no longer any indication of an active infection. Studies have found that a portion of the bacterial cell wall from the causative agent, Borrelia burgdorferi, is a persistent antigen in Lyme arthritis patients, lingering within the synovial fluid. This antigen, peptidoglycan, is recognized by the immune system in numerous ways. Multiple publications have shown that peptidoglycan is proinflammatory and can cause arthritis when injected in vivo. The same was found to be true for B. burgdorferi peptidoglycan. Studies focused on the structure of peptidoglycan from B. burgdorferi have shown atypical differences in both glycan and peptide chemistry that likely alter immune recognition.

• #35 Lyme Disease Pathogenesis – PubMed

  https://pubmed.ncbi.nlm.nih.gov/33353871/

  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. […] To evade complement, Lyme disease spirochetes produce outer surface lipoproteins that interfere with host complement by inhibiting complement activity directly or binding to host-derived regulators of complement activity (RCA). […] Several Borrelia inhibitors block the upstream initiation steps, including the CP-specific inhibitor BBK32, which binds to C1r and traps C1 in a zymogen state. […] Lyme disease spirochetes also produce p43, which downregulates the CP and LP by recruiting the RCA called C4b-binding protein (C4BP). […] Proteins known to affect experimental infection by B. burgdorferi are outlined in blue, those that are important in transmission from Ixodes ticks are framed in green, and those whose functions in vivo are not defined are shown in red.

• #36 Other News | Tufts Lyme Disease Initiative

  https://tuftslymedisease.org/archives/

  A central question in Lyme disease pathogenesis is why neutrophils, which are highly efficient killers of B. burgdorferi, are initially attracted to the erythema migrans rash but then disappear over the period of a day. This manuscript by Muldur et al show the role that complement plays in attracting neutrophils. […] Tick-borne diseases affecting humans and animals are on the rise worldwide. Vaccines constitute an effective control measure, but very few are available. We selected Lyme borreliosis, a bacterial infection transmitted by the hard tick Ixodes, to validate a new concept to identify vaccine candidates. This disease is the most common tick-borne disease in the Northern Hemisphere.

• #37 Lyme disease – Wikipedia

  https://en.wikipedia.org/wiki/Lyme_disease

  Exposure to the Borrelia bacterium during Lyme disease possibly causes a long-lived and damaging inflammatory response, a form of pathogen-induced autoimmune disease. […] The production of this reaction might be due to a form of molecular mimicry, where Borrelia avoids being killed by the immune system by resembling normal parts of the body’s tissues. […] Chronic symptoms from an autoimmune reaction could explain why some symptoms persist even after the spirochetes have been eliminated from the body. This hypothesis may explain why chronic arthritis persists after antibiotic therapy, similar to rheumatic fever, but its wider application is controversial.

• #38 Lyme Disease: Practice Essentials, Background, Etiology

  https://emedicine.medscape.com/article/330178-overview

  Antibodies against spirochetal protein membrane epitopes have been shown to cross-react with neural and connective tissues. […] This molecular mimicry possibly generates an autoimmune inflammatory reaction. […] The organism also can persist in the skin for very long periods. […] The spirochete can penetrate human fibroblasts and live intracellularly, even when the extracellular medium contains ceftriaxone at concentrations well above bactericidal levels.

• #39 Pathogenesis, Diagnosis and Treatment of Lyme and other Tick-borne Diseases | Frontiers Research Topic

  https://www.frontiersin.org/research-topics/10848/pathogenesis-diagnosis-and-treatment-of-lyme-and-other-tick-borne-diseases/magazine

  Lyme disease is the most common tick-borne disease with an estimated 300,000 cases per year in the United States. It has long been known that Lyme disease is caused by certain species of spirochetes from the Borrelia burgdorferi (sensu lato) complex. Despite recent advances in understanding the molecular pathogenesis of the Lyme disease though, infection with these pathogens remains difficult to diagnose and treat. […] Signals that Borrelia spirochetes receive from hostile environments evoke morphological alterations to round bodies, tiny granular forms, and microcolonies, that keep the pathogen alive and induce the production of antibiotic-tolerant persister cells, which are refractory to antibiotic elimination. These metamorphoses could contribute significantly to treatment failures, as Borrelia is able to modulate and suppress host immune system which can further affect serodiagnosis and treatment outcome.

• #40 Round bodies, blebs and biofilms in Lyme disease – Daniel Cameron MD

  https://danielcameronmd.com/bio%EF%AC%81lms-in-lyme-disease/

  In an effort to better understand their significance, Corak and colleagues grew B. burgdorferi spirochete, round body, bleb, and biofilm-dominated cultures and recovered their transcriptomes by RNAseq profiling. Their non-spirochete morphotypes were induced by simple changes in growth conditions. […] The authors postulated, These regularities point to the possibility that bleb and biolm morphotypes might be important in the dissemination and persistence of B. burgdorferi inside the mammalian host. […] They encouraged further research regarding the function of a large number of genes that might explain the pathogenesis of Lyme disease. […] Taken together, we believe that many of the ongoing controversies related to Lyme disease pathogenesis and treatment strategies could be resolved by improving our understanding of B. burgdorferi biology and evolution, which for unclear reasons have not yet been explored.

• #41 Borrelia burgdorferi, the Lyme disease spirochete, possesses genetically-encoded responses to doxycycline, but not to amoxicillin | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0274125

  Those concentrations were designated sublethal, and were subsequently tested for their effects on cell morphology and gene expression in B. burgdorferi. […] Exposure of B. burgdorferi to 0.2 g/ml doxycycline led to an initial significant decrease in expression of 36 genes after three hours compared to control cells without antibiotics, while no genes were significantly increased at this timepoint. […] These gene expression changes indicate that B. burgdorferi possesses a genetically-encoded mechanism(s) that attempts to overcome ribosome impairment, which is focused on enhanced production of mRNAs for components of translation. […] The absence of cell wall-directed responses to amoxicillin suggests that B. burgdorferi may lack a mechanism to assess cell wall integrity. […] Our data also suggest that B. burgdorferi does not naturally encounter other conditions that block peptidoglycan synthesis, and thus has not evolved mechanisms to respond to such a stress.

• #42 Borrelia burgdorferi, the Lyme disease spirochete, possesses genetically-encoded responses to doxycycline, but not to amoxicillin | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0274125

  In contrast, B. burgdorferi evidently possesses a mechanism(s) that detects the impairment of translation due to doxycycline, and attempts to overcome that inhibition by increasing expression of genes involved with translation. […] Taken together, our studies found that B. burgdorferi demonstrates distinct responses to different antibiotics.

• #43 Pathogenesis, Diagnosis and Treatment of Lyme and other Tick-borne Diseases | Frontiers Research Topic

  https://www.frontiersin.org/research-topics/10848/pathogenesis-diagnosis-and-treatment-of-lyme-and-other-tick-borne-diseases/magazine

  The pathobiology of PTLDS is poorly understood, and its therapy remains a contentious issue, as there is currently no FDA-approved treatment. Prolonged treatment of persistent Lyme disease with the current Lyme antibiotics have limited effect and could have potential side effects. More effective therapies and new therapeutic approaches are urgently needed. The recent identification of FDA-approved drug candidates that are active against Borrelia persister cells and their combination with existing Lyme antibiotics, could completely eradicate Borrelia persister cells in vitro and in animal models and may provide a more effective treatment of persistent Lyme disease. […] Overall in this Research Topic, we aim to better understand the role of microbial persisters and the host immune responses, and to identify biomarkers associated with PTLDS. We also welcome manuscripts that refer to molecular pathogenesis and pathophysiology of Lyme disease and further address the role of co-infection microbes.

• #44 Lyme disease – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/lyme-disease/symptoms-causes/syc-20374651

  Lyme disease is an illness caused by borrelia bacteria. Humans usually get Lyme disease from the bite of a tick carrying the bacteria. […] Lyme disease is caused by borrelia bacteria. In North America, the black-legged tick, also called the deer tick, mainly carry the bacteria. […] Ticks pick up bacteria from a host, such as a deer or rodent. They don’t get sick. But they can pass the bacteria to another host. When an infected tick feeds on a person, the bacteria can move to the person’s bloodstream. The bacteria are less likely to spread Lyme disease if you remove the tick within 24 hours. […] These longer-lasting symptoms may include: Arthritis that begins with Lyme disease and doesn’t improve. […] These long-lasting problems may be caused by: Incomplete treatment. […] Immune system response to fragments of killed bacteria. […] Immune system activity that harms healthy tissues, also called autoimmunity.

• #45

  https://www.jci.org/articles/view/138062

  Thus, high numbers of IFN-producing cells in synovia may prevent repair of tissue damaged by the infection, blocking the return to tissue homeostasis even after spirochetal killing. […] The pathogenesis of PTLDS is not well understood. […] Rather, with infection, the brain is sensitized to pain signals, an alarm signal, and fatigue necessitates rest. […] One hypothesis is that in patients with PTLDS the enhanced sensory signals during the infection do not reset after infection, and the increased sensitivity to pain, brain fog, and marked fatigue persist, called a central sensitization syndrome. […] Disabling posttreatment syndromes may still develop, which appear to result primarily from disadvantageous or maladaptive host responses to the infection that persist after spirochetal killing with antibiotics.

• #46 Report of the Pathogenesis and Pathophysiology of Lyme Disease Subcommittee to the Tick-Borne Disease Working Group | Health.govLock

  https://www.hhs.gov/ash/advisory-committees/tickbornedisease/reports/pathogenesis-pathophysiology-lyme-disease-subcomm-2020/index.html

  What underlies the persistence of Borrelia in host tissues? […] Does immune evasion or suppression or autoimmunity contribute to the process of persistent symptoms? […] Is there a role for antibiotic tolerance in “resistance” to successful antibiotic treatment? […] It has been established that the causative organism of Lyme disease, B. burgdorferi, can persist in a number of animal models and human case studies following infection and treatment with a “standard” course of antibiotics. […] The mechanisms underlying the establishment and persistence of B. burgdorferi following experimental infection are beginning to be delineated, but gaps still exist in our understanding of this process, which gaps of information contribute to problems in the care of patients with persistent Lyme disease.

• #47 Faculty Collaboration Database – Report of the Pathogenesis and Pathophysiology of Lyme Disease Subcommittee of the HHS Tick Borne Disease Working Group. Front Med (Lausanne) 2021;8:643235

  https://fcd.mcw.edu/?search/showPublication/id/1572982

  An understanding of the pathogenesis and pathophysiology of Lyme disease is key to the ultimate care of patients with Lyme disease. […] To better understand the various mechanisms underlying the infection caused by Borrelia burgdorferi, the Pathogenesis and Pathophysiology of Lyme Disease Subcommittee was formed to review what is currently known about the pathogenesis and pathophysiology of Lyme disease, from its inception, but also especially about its ability to persist in the host. […] To that end, the authors of this report were assembled to update our knowledge about the infectious process, identify the gaps that exist in our understanding of the process, and provide recommendations as to how to best approach solutions that could lead to a better means to manage patients with persistent Lyme disease.

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