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

Abstract

BackgroundLyme neuroborreliosis (LNB), caused by the spirochete Borrelia burgdorferi, affects both the peripheral and the central nervous systems. Radiculitis or nerve root inflammation, which can cause pain, sensory loss, and weakness, is the most common manifestation of peripheral LNB in humans. We previously reported that rhesus monkeys infected with B. burgdorferi develop radiculitis as well as inflammation in the dorsal root ganglia (DRG), with elevated levels of neuronal and satellite glial cell apoptosis in the DRG. We hypothesized that B. burgdorferi induces inflammatory mediators in glial and neuronal cells and that this inflammatory milieu precipitates glial and neuronal apoptosis.MethodsTo model peripheral neuropathy in LNB we incubated normal rhesus DRG tissue explants with live B. burgdorferi ex vivo and identified immune mediators, producer cells, and verified the presence of B. burgdorferi in tissue sections by immunofluorescence staining and confocal microscopy. We also set up primary cultures of DRG cells from normal adult rhesus macaques and incubated the cultures with live B. burgdorferi. Culture supernatants were subjected to multiplex ELISA to detect immune mediators, while the cells were evaluated for apoptosis by the in situ TUNEL assay. A role for inflammation in mediating apoptosis was assessed by evaluating the above phenomena in the presence and absence of various concentrations of the anti-inflammatory drug dexamethasone. As Schwann cells ensheath the dorsal roots of the DRG, we evaluated the potential of live B. burgdorferi to induce inflammatory mediators in human Schwann cell (HSC) cultures.ResultsRhesus DRG tissue explants exposed to live B. burgdorferi showed localization of CCL2 and IL-6 in sensory neurons, satellite glial cells and Schwann cells while IL-8 was seen in satellite glial cells and Schwann cells. Live B. burgdorferi induced elevated levels of IL-6, IL-8 and CCL2 in HSC and DRG cultures and apoptosis of sensory neurons. Dexamethasone reduced the levels of immune mediators and neuronal apoptosis in a dose dependent manner.ConclusionIn this model, B. burgdorferi induced an inflammatory response and neuronal apoptosis of DRG. These pathophysiological processes could contribute to peripheral neuropathy in LNB.

New records of the Lyme disease bacterium in ticks collected from songbirds in central and eastern Canada

“…In particular, B. burgdorferi-infected I. scapularis can initiate Lyme disease in humans causing a myriad of symptoms (Cameron et al 2014;Adrion et al 2015). Without early or adequate treatment, Lyme disease patients may develop a latent infection because spirochetes will invade and lodge in immune-privileged sites and deep-seated tissues, such as tendons and ligaments (Häupl et al 1993;Müller 2012), brain (Oksi et al 1996;MacDonald 2007;Miklossy 2011), bone (Oksi et al 1994;Fein and Tilton 1997), muscle (Frey et al 1998), eye (Preac-Mursic et al 1993, glial and neuronal cells (Ramesh et al 2008(Ramesh et al , 2013 and fibroblasts/scar tissue (Klempner et al 1993). In these secluded niches, B. burgdorferi can flourish and, a clinically non-apparent infection, can progress to manifest disease due to the combined effects of a persistent infection and the ensuing inflammatory responses.…”

Membrane Fluidity: About the Origin of Autoimmunity

“…This gives an advantage to the bacterium. In that, the immune response works suboptimal [14]. In addition, cells might become leaky, releasing amino acids and other nutrients to the extracellular liquid, feeding the bacteria.…”

The Putative Role of Viruses, Bacteria, and Chronic Fungal Biotoxin Exposure in the Genesis of Intractable Fatigue Accompanied by Cognitive and Physical Disability

“…The interaction of primary brain parenchymal cells with the spirochete provokes the release of IL-6, IL-8, TNFα, and cyclooxygenase 2 (COX-2) from glial cells, as well as inducing glial and neuronal apoptosis [216]. It is also noteworthy that Bf infection induces cellular apoptosis in the dorsal root ganglion [217]. Activation of microglia by engagement of TLR1, TLR2, and CD19 on the surface of these glial cells is another major source of neuroinflammatory mediators such as NF-κB, PGE2, proinflammatory cytokines, and IL-6, whose chronic presence leads to neuronal apoptosis and the elevation of p53 [218,219].…”