<i>Borrelia burgdorferi</i>peptidoglycan is a persistent antigen in patients with Lyme arthritis

Jutras, Brandon L.; Lochhead, Robert B.; Kloos, Zachary A.; Biboy, Jacob; Strle, Klemen; Booth, Carmen J.; Govers, Sander K.; Gray, Joe; Schümann, Peter; Vollmer, Waldemar; Bockenstedt, Linda K.; Steere, Allen C.

doi:10.1073/pnas.1904170116

Cited by 126 publications

(179 citation statements)

References 92 publications

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“…Another hypothesis is an extended immune response created by the continued presence of antigenic debris or immunogenic peptidoglycans shed from B. burgdorferi [59,60]. However, the fact that this patient was treated extensively during an illness of 16 years argues against that idea, and it is unlikely that debris could persist for that period of time.…”

Section: Borrelia Antigens and Dna Are Associated With Biofilmsmentioning

confidence: 98%

The Long-Term Persistence of Borrelia burgdorferi Antigens and DNA in the Tissues of a Patient with Lyme Disease

et al. 2019

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Whether Borrelia burgdorferi, the causative agent of Lyme disease, can persist for long periods in the human body has been a controversial question. The objective of this study was to see if we could find B. burgdorferi in a Lyme disease patient after a long clinical course and after long-term antibiotic treatment. Therefore, we investigated the potential presence of B. burgdorferi antigens and DNA in human autopsy tissues from a well-documented serum-, PCR-, and culture-positive Lyme disease patient, a 53-year-old female from northern Westchester County in the lower Hudson Valley Region of New York State, who had received extensive antibiotic treatments during extensive antibiotic treatments over the course of her 16-year-long illness. We also asked what form the organism might take, with special interest in the recently found antibiotic-resistant aggregate form, biofilm. We also examined the host tissues for the presence of inflammatory markers such as CD3+ T lymphocytes. Autopsy tissue sections of the brain, heart, kidney, and liver were analyzed by histological and immunohistochemical methods (IHC), confocal microscopy, fluorescent in situ hybridization (FISH), polymerase chain reaction (PCR), and whole-genome sequencing (WGS)/metagenomics. We found significant pathological changes, including borrelial spirochetal clusters, in all of the organs using IHC combined with confocal microscopy. The aggregates contained a well-established biofilm marker, alginate, on their surfaces, suggesting they are true biofilm. We found B. burgdorferi DNA by FISH, polymerase chain reaction (PCR), and an independent verification by WGS/metagenomics, which resulted in the detection of B. burgdorferi sensu stricto specific DNA sequences. IHC analyses showed significant numbers of infiltrating CD3+ T lymphocytes present next to B. burgdorferi biofilms. In summary, we provide several lines of evidence that suggest that B. burgdorferi can persist in the human body, not only in the spirochetal but also in the antibiotic-resistant biofilm form, even after long-term antibiotic treatment. The presence of infiltrating lymphocytes in the vicinity of B. burgdorferi biofilms suggests that the organism in biofilm form might trigger chronic inflammation.

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Section: Borrelia Antigens and Dna Are Associated With Biofilmsmentioning

confidence: 98%

The Long-Term Persistence of Borrelia burgdorferi Antigens and DNA in the Tissues of a Patient with Lyme Disease

et al. 2019

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“…The actual molecular component of Bb that initiates JHR in Lyme patients is currently unknown, and the reaction in Lyme patients is usually reported in the literature as being mild relative to other infections. One conceivable cause of increased symptoms and serum cytokine levels post-treatment is the release of immunologically reactive fragments generated by antibiotic-induced cellular destruction [295], including peptidoglycan [296,297]. Understanding the root cause of the JHR would lead to treatments that reduce or eliminate these episodes.…”

Section: Clinical Antibiotic Treatmentmentioning

confidence: 99%

Lyme Disease Frontiers: Reconciling Borrelia Biology and Clinical Conundrums

Bamm

Mainprize

et al. 2019

Pathogens

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Lyme disease is a complex tick-borne zoonosis that poses an escalating public health threat in several parts of the world, despite sophisticated healthcare infrastructure and decades of effort to address the problem. Concepts like the true burden of the illness, from incidence rates to longstanding consequences of infection, and optimal case management, also remain shrouded in controversy. At the heart of this multidisciplinary issue are the causative spirochetal pathogens belonging to the Borrelia Lyme complex. Their unusual physiology and versatile lifestyle have challenged microbiologists, and may also hold the key to unlocking mysteries of the disease. The goal of this review is therefore to integrate established and emerging concepts of Borrelia biology and pathogenesis, and position them in the broader context of biomedical research and clinical practice. We begin by considering the conventions around diagnosing and characterizing Lyme disease that have served as a conceptual framework for the discipline. We then explore virulence from the perspective of both host (genetic and environmental predispositions) and pathogen (serotypes, dissemination, and immune modulation), as well as considering antimicrobial strategies (lab methodology, resistance, persistence, and clinical application), and borrelial adaptations of hypothesized medical significance (phenotypic plasticity or pleomorphy).

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“…B. burgdorferi also expresses peptidoglycans, which may be recognized by the human immune system. Recently, human IgG responses against B. burgdorferi peptidoglycan have been related to worsening of Lyme arthritis in the long term …”

Section: From Skin Invasion To Articular Joints: Initiation Of Lyme Amentioning

confidence: 99%

“…Recently, human IgG responses against B. burgdorferi peptidoglycan have been related to worsening of Lyme arthritis in the long term. 64 After adhering to the endothelium, B. burgdorferi traverses the endothelial cell monolayers through tight junctions. 65,66 Borrelia P66 protein can form an OM β-barrel porin that adheres to host β1 and β3 chain integrins.…”

Section: From S K In Inva S I On To Arti Cul Ar Joints: Initiati Onmentioning

confidence: 99%

A joint effort: The interplay between the innate and the adaptive immune system in Lyme arthritis

Brouwer

Schoor

Vrijmoeth

et al. 2020

Immunological Reviews

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Articular joints are a major target of Borrelia burgdorferi, the causative agent of Lyme arthritis. Despite antibiotic treatment, recurrent or persistent Lyme arthritis is observed in a significant number of patients. The host immune response plays a crucial role in this chronic arthritic joint complication of Borrelia infections. During the early stages of B. burgdorferi infection, a major hinder in generating a proper host immune response is the lack of induction of a strong adaptive immune response. This may lead to a delayed hyperinflammatory reaction later in the disease. Several mechanisms have been suggested that might be pivotal for the development of Lyme arthritis and will be highlighted in this review, from molecular mimicry of matrix metallopeptidases and glycosaminoglycans, to autoimmune responses to live bacteria, or remnants of Borrelia spirochetes in joints. Murine studies have suggested that the inflammatory responses are initiated by innate immune cells, but this does not exclude the involvement of the adaptive immune system in this dysregulated immune profile. Genetic predisposition, via human leukocyte antigen‐DR isotype and microRNA expression, has been associated with the development of antibiotic‐refractory Lyme arthritis. Yet the ultimate cause for (antibiotic‐refractory) Lyme arthritis remains unknown. Complex processes of different immune cells and signaling cascades are involved in the development of Lyme arthritis. When these various mechanisms are fully been unraveled, new treatment strategies can be developed to target (antibiotic‐refractory) Lyme arthritis more effectively.

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Borrelia burgdorferipeptidoglycan is a persistent antigen in patients with Lyme arthritis

Cited by 126 publications

References 92 publications

The Long-Term Persistence of Borrelia burgdorferi Antigens and DNA in the Tissues of a Patient with Lyme Disease

The Long-Term Persistence of Borrelia burgdorferi Antigens and DNA in the Tissues of a Patient with Lyme Disease

Lyme Disease Frontiers: Reconciling Borrelia Biology and Clinical Conundrums

A joint effort: The interplay between the innate and the adaptive immune system in Lyme arthritis

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