Pathogenesis of Lyme neuroborreliosis: Borrelia burgdorferi lipoproteins induce both proliferation and apoptosis in rhesus monkey astrocytes

  title={Pathogenesis of Lyme neuroborreliosis: Borrelia burgdorferi lipoproteins induce both proliferation and apoptosis in rhesus monkey astrocytes},
  author={Geeta Ramesh and Alida L. Alvarez and Edgar Donald Roberts and Vida A Dennis and Barbara L. Lasater and Xavier Alvarez and Mario T. Philipp},
  journal={European Journal of Immunology},
Brain invasion by Borrelia burgdorferi, the agent of Lyme disease, results in an inflammatory and neurodegenerative disorder called neuroborreliosis. In humans, neuroborreliosis has been correlated with enhanced concentration of glial fibrillary acidic protein in the cerebrospinal fluid, a sign of astrogliosis. Rhesus monkeys infected by us with B. burgdorferi showed evidence of astrogliosis, namely astrocyte proliferation and apoptosis. We formulated the hypothesis that astrogliosis could be… 

Interaction of the Lyme disease spirochete Borrelia burgdorferi with brain parenchyma elicits inflammatory mediators from glial cells as well as glial and neuronal apoptosis.

Results provide proof of concept for the hypothesis that B. burgdorferi induces the production of inflammatory mediators in the central nervous system with concomitant neuronal and/or glial apoptosis, accompanied by glial and neuronal apoptosis.

The Lyme disease spirochete Borrelia burgdorferi induces inflammation and apoptosis in cells from dorsal root ganglia

To model peripheral neuropathy in LNB, B. burgdorferi induced an inflammatory response and neuronal apoptosis of DRG in a dose dependent manner and dexamethasone reduced the levels of immune mediators and neurons apoptosis in adose dependent manner.

Invasion of human neuronal and glial cells by an infectious strain of Borrelia burgdorferi.

Toll-Like Receptors: Insights into Their Possible Role in the Pathogenesis of Lyme Neuroborreliosis

Data provide proof of the concept that astrocyte and microglial TLR1, -2, and -5 are involved in the in vivo response of primate glial cells to B. burgdorferi, and could be a significant factor in the pathogenesis of Lyme neuroborreliosis.

Possible role of glial cells in the onset and progression of Lyme neuroborreliosis

The results support the notion that innate responses of glia to B. burgdorferi initiate/mediate the inflammation seen in acute LNB, and show that neuronal apoptosis occurs in this context.

The multifaceted responses of primary human astrocytes and brain microvascular endothelial cells to the Lyme disease spirochete, Borrelia burgdorferi

The results demonstrate that primary astrocytes and HBMEC respond to virulent B. burgdorferi by producing a number of chemokines, and suggest that infiltrating phagocytic cells, particularly neutrophils, attracted byChemokines expressed at the BBB (blood–brain barrier) may be important contributors to the early inflammatory events associated with neuroborreliosis.

Toll-Like Receptors: Insights into Their Possible Role in the Pathogenesis of Lyme Neuroborreliosis (cid:1)

The data provide proof of the concept that astrocyte and microglial TLR1, -2, and -5 are involved in the in vivo response of primate glial cells to B. burgdorferi, and it is hypothesized that these TLR-mediated responses could be a signif-icant factor in the pathogenesis of Lyme neuroborreliosis.

Microglia Are Mediators of Borrelia burgdorferi–Induced Apoptosis in SH-SY5Y Neuronal Cells

Findings indicate that B. burgdorferi is not directly toxic to SY cells; rather, these cells become distressed and die in the inflammatory surroundings generated by microglia through a bystander effect, and targeting microglial responses may be a significant therapeutic approach for the treatment of this form of Lyme disease.

Brucella abortus induces the secretion of proinflammatory mediators from glial cells leading to astrocyte apoptosis.

In vivo and in vitro evidence that B. abortus and its lipoproteins activate the innate immunity of the CNS, eliciting an inflammatory response that leads to astrogliosis, a characteristic feature of neurobrucellosis is presented.



Pathogenesis of Lyme neuroborreliosis in the rhesus monkey: the early disseminated and chronic phases of disease in the peripheral nervous system.

The histopathologic and immunohistochemical features of early and late neuroborreliosis of the peripheral nervous system were investigated in rhesus macaques infected with the JD1 strain of Borrelia burgdorferi and possible mechanisms to explain the appearance and subsidence of Lyme neuritis are discussed.

Localization of Borrelia Burgdorferi in the Nervous System and Other Organs in a Nonhuman Primate Model of Lyme Disease

The results showed that the number of spirochetes was significantly higher in immunosuppressed animals, and B. burgdorferi has a tropism for the meninges in the CNS and for connective tissues elsewhere in the body.

Inoculation of nonhuman primates with the N40 strain of Borrelia burgdorferi leads to a model of lyme neuroborreliosis faithful to the human disease

These studies are the first to demonstrate that experimental LNB in NHPs is a reliable model faithful to the human disease, with spirochetal invasion of the subarachnoid space, and the first report of CSF samples positive by culture in experimental L NB.

Treponema pallidum and Borrelia burgdorferi lipoproteins and synthetic lipopeptides activate monocytes/macrophages.

The potential for spirochetal lipoproteins to function as general macrophage activators was demonstrated by the ability of the synthetic analogues to induce IL-1 beta, IL-6, and IL-12, in addition to TNF, in murine and/or human macrophages.

Borrelia burgdorferi outer surface protein A (OspA) activates and primes human neutrophils.

Examining the effect of OspA on the activities of the neutrophil found that it could prime neutrophils for FMLP-induced release of lysosomal granules and production of superoxide, like LPS and FMLP.

Adherence of the Lyme disease spirochete to glial cells and cells of glial origin.

Lyme disease, a tick-borne spirochetosis caused by Borrelia burgdorferi, produces protean neurologic manifestations, yet its neuropathogenesis is poorly understood andherence of the spirochetes to the glial components of the primary brain culture could be an early event in the production of neurological injury.

Borrelia burgdorferi outer membrane protein A induces nuclear translocation of nuclear factor-kappa B and inflammatory activation in human endothelial cells.

Outward surface protein A (OspA), a model B. burgdorferi lipoprotein, was found to be a potent stimulant of nuclear factor-kappa B (NF- kappa B) nuclear translocation in human endothelial cells, resulting in nuclear levels similar to those seen in response to known inflammatory mediators.

Borrelia burgdorferi Stimulates the Production of Interleukin-10 in Peripheral Blood Mononuclear Cells from Uninfected Humans and Rhesus Monkeys

It is demonstrated that B. burgdorferi can stimulate the production of an antiinflammatory, immunosuppressive cytokine in naive cells and suggested that IL-10 may play a role both in avoidance by the spirochete of deleterious immune responses and in limiting the inflammation that the spirachete is able to induce.

Neuroborreliosis in the nonhuman primate: Borrelia burgdorferi persists in the central nervous system

Data suggest that Lyme neuroboreliosis represents persistent infection with B. burgdorferi in the central nervous system, and that the organism has a predilection toward subtentorial structures.

Lipoproteins of Borrelia burgdorferi and Treponema pallidum activate cachectin/tumor necrosis factor synthesis. Analysis using a CAT reporter construct.

Through their ability to induce TNF production by macrophages, spirochete lipoproteins may play important roles in the development of the local inflammatory changes and the systemic manifestations that characterize syphilis and Lyme disease.