3D blood-brain barrier-organoids as a model for Lyme neuroborreliosis highlighting genospecies dependent organotropism

Adams, Yvonne; Clausen, Anne Skovsbo; Jensen, Peter Østrup; Lager, Malin; Wilhelmsson, Peter; Henningson, Anna J.; Lindgren, Per-Eric; Faurholt‐Jepsen, Daniel; Mens, Helene; Kraiczy, Peter; Kragh, Kasper Nørskov; Bjarnsholt, Thomas; Kjær, Andreas; Lebech, Anne-Mette; Jensen, Anja Ramstedt

doi:10.1016/j.isci.2022.105838

Cited by 8 publications

(11 citation statements)

References 63 publications

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“…It is tempting to speculate that some kind of competition might occur between the spirochete species in the process of crossing the BBB, and this might be the basis of our observations. A recent study by Adams and colleagues (27) showed that different species of LD spirochetes are able to enter BBB-organoids with different rates of success. The spirochetes that successfully invaded the organoids remained viable inside the BBB-organoids, initiating the loss of tight junction and changes in the organoids gross morphology and integrity (27).…”

Section: Discussionmentioning

confidence: 99%

“…A recent study by Adams and colleagues (27) showed that different species of LD spirochetes are able to enter BBB-organoids with different rates of success. The spirochetes that successfully invaded the organoids remained viable inside the BBB-organoids, initiating the loss of tight junction and changes in the organoids gross morphology and integrity (27). To our knowledge, this is the first study that confirms the presence of B. garinii and B. burgdorferi s.s. structures in the human brain with strict separation of invaded brain loci.…”

Section: Discussionmentioning

confidence: 99%

“…The most frequent manifestation of B. burgdorferi s.s. induced neuroborreliosis in the United States is lymphocytic meningitis whereas European B. gariniiinduced LNB, in the majority of cases, is diagnosed as subacute painful meningoradiculitis or cranial nerve palsy, a uncommon manifestation of LNB in the USA (26). Such differences in clinical manifestations of LNB, caused by different spirochete species might be based on different mechanisms of dissemination of the bacterial pathogen into the nervous system, different capabilities of individual species to cross the blood-brain barrier (BBB) by either by transcellular or paracellular penetration (27), or different diagnostic protocols. Until recently, no reliable system for the detection of persistent infection exists.…”

Section: Introductionmentioning

confidence: 99%

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Concurrent infection of human brain with multiple species of Lyme disease spirochetes

Golovchenko

Opelka

Vancová

et al. 2023

Preprint

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Lyme disease (LD) spirochetes are well known to be able to disseminate into the tissues of infected hosts, including humans. The diverse strategies used by spirochetes to avoid the host immune system and persist in the host include active immune suppression, induction of immune tolerance, phase and antigenic variation, intracellular seclusion, and, importantly, incursion into immune privileged sites such as the brain. Invasion of immune privileged sites, like the brain allows the spirochetes not only escape from the host immune system but also can reduce the efficacy of antibiotic therapy. Here we present a case of the detection of DNA of spirochetes from Borrelia burgdorferi sensu lato complex from multiple loci of LD patient’s post-mortem brain. The presence of co-infection with Borrelia burgdorferi sensu stricto and Borrelia garinii in LD patient’s brain was confirmed by PCR. The presence of atypical spirochete morphology was confirmed by immunohistochemistry of the brain samples and also in tissues of experimental mice, infected with Borrelia by simultaneous injection of spirochetes subcutaneously and intraperitoneally. Even though both spirochete species were simultaneously present in brain, the brain regions where the two species were detected were different and non-overlapping.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Concurrent infection of human brain with multiple species of Lyme disease spirochetes

Golovchenko

Opelka

Vancová

et al. 2023

Preprint

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“…180 Similarly, relationships between the BBB and Plasmodium falciparum and Lyme neuroborreliosis were explored via BBB organoids. 181,182 Bartfeld et al 183 successfully established Helicobacter pylori (Hp)-infected human gastric organoids, and inflammatory responses were observed in these infected organoid cells. The adhesion of Hp depends on the high affinity between the TlpB receptor and urea secreted by gastric cells, and Hp is likely to attach to highly differentiated pit cells with a larger volume.…”

Section: Infectious Diseasesmentioning

confidence: 99%

“…Cryptosporidium infected human small intestinal and lung organoids have been established 180 . Similarly, relationships between the BBB and Plasmodium falciparum and Lyme neuroborreliosis were explored via BBB organoids 181,182 . Bartfeld et al 183 .…”

Section: Biomedical Applications Of Organoidsmentioning

confidence: 99%

Organoids: The current status and biomedical applications

Yang

Kung

et al. 2023

MedComm

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Organoids are three‐dimensional (3D) miniaturized versions of organs or tissues that are derived from cells with stem potential and can self‐organize and differentiate into 3D cell masses, recapitulating the morphology and functions of their in vivo counterparts. Organoid culture is an emerging 3D culture technology, and organoids derived from various organs and tissues, such as the brain, lung, heart, liver, and kidney, have been generated. Compared with traditional bidimensional culture, organoid culture systems have the unique advantage of conserving parental gene expression and mutation characteristics, as well as long‐term maintenance of the function and biological characteristics of the parental cells in vitro. All these features of organoids open up new opportunities for drug discovery, large‐scale drug screening, and precision medicine. Another major application of organoids is disease modeling, and especially various hereditary diseases that are difficult to model in vitro have been modeled with organoids by combining genome editing technologies. Herein, we introduce the development and current advances in the organoid technology field. We focus on the applications of organoids in basic biology and clinical research, and also highlight their limitations and future perspectives. We hope that this review can provide a valuable reference for the developments and applications of organoids.

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Bridging the gap: Insights in the immunopathology of Lyme borreliosis

Snik,

Stouthamer,

Hovius

et al. 2024

Eur J Immunol

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Lyme borreliosis (LB), caused by Borrelia burgdorferi sensu lato (Bbsl) genospecies transmitted by Ixodes spp. ticks, is a significant public health concern in the Northern Hemisphere. This review highlights the complex interplay between Bbsl infection and host–immune responses, impacting clinical manifestations and long‐term immunity. Early localized disease is characterized by erythema migrans (EM), driven by T‐helper 1 (Th1) responses and proinflammatory cytokines. Dissemination to the heart and CNS can lead to Lyme carditis and neuroborreliosis respectively, orchestrated by immune cell infiltration and chemokine dysregulation. More chronic manifestations, including acrodermatitis chronica atrophicans and Lyme arthritis, involve prolonged inflammation as well as the development of autoimmunity. In addition, dysregulated immune responses impair long‐term immunity, with compromised B‐cell memory and antibody responses. Experimental models and clinical studies underscore the role of Th1/Th2 balance, B‐cell dysfunction, and autoimmunity in LB pathogenesis. Moreover, LB‐associated autoimmunity parallels mechanisms observed in other infectious and autoimmune diseases. Understanding immune dysregulation in LB provides insights into disease heterogeneity and could provide new strategies for diagnosis and treatment.

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3D blood-brain barrier-organoids as a model for Lyme neuroborreliosis highlighting genospecies dependent organotropism

Cited by 8 publications

References 63 publications

Concurrent infection of human brain with multiple species of Lyme disease spirochetes

Concurrent infection of human brain with multiple species of Lyme disease spirochetes

Organoids: The current status and biomedical applications

Bridging the gap: Insights in the immunopathology of Lyme borreliosis

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