The Multifaceted Responses of Primary Human Astrocytes and Brain Microvascular Endothelial Cells to the Lyme Disease Spirochete, Borrelia Burgdorferi

Abstract

The vector-borne pathogen, Borrelia burgdorferi, causes a multi-system disorder including neurological complications. These neurological disorders, collectively termed neuroborreliosis, can occur in up to 15% of untreated patients. The neurological symptoms are probably a result of a glial-driven, host inflammatory response to the bacterium. However, the specific contributions of individual glial and other support cell types to the pathogenesis of neuroborreliosis are relatively unexplored. The goal of this project was to characterize specific astrocyte and endothelial cell responses to B. burgdorferi. Primary human astrocytes and primary HBMEC (human brain microvascular endothelial cells) were incubated with B. burgdorferi over a 72-h period and the transcriptional responses to the bacterium were analyzed by real-time PCR arrays. There was a robust increase in several surveyed chemokine and related genes, including IL (interleukin)-8, for both primary astrocytes and HBMEC. Array results were confirmed with individual sets of PCR primers. The production of specific chemokines by both astrocytes and HBMEC in response to B. burgdorferi, including IL-8, CXCL-1, and CXCL-10, were confirmed by ELISA. These results demonstrate that primary astrocytes and HBMEC respond to virulent B. burgdorferi by producing a number of chemokines. These data suggest that infiltrating phagocytic cells, particularly neutrophils, attracted by chemokines expressed at the BBB (blood–brain barrier) may be important contributors to the early inflammatory events associated with neuroborreliosis.

Neutrophil Extracellular Traps (NETs) in the Cerebrospinal Fluid Samples from Children and Adults with Central Nervous System Infections

“…The finding of neutrophil activation in both LNB and EVM is intriguing, since these infections have similarities with respect to both clinical presentation and CSF cellular profile, which may include neutrophil predominance in the early phase [35]. Several studies have de facto shown the presence of neutrophil-activating cytokines and chemokines in the CSF samples of patients with LNB [36][37][38][39] and EVM [40,41], and the production of neutrophil chemo-attractants, such as CXCL1, CXCL8 and CXCL10 after in vitro stimulation of neuronal cells in response to B. burgdorferi spirochaetes [42]. Thus, there appears to be a prerequisite for neutrophil recruitment into the CNS in infections caused by B. burgdorferi and enterovirus.…”

Translational potential of astrocytes in brain disorders

“…Direct incubation of astrocytes with the gram-negative Borrelia burgdorferi up-regulated synthesis and release of the matrix metalloprotease 9, that could contribute to the disruption of the blood-brain barrier (Perides et al ., 1999). In addition, an exposure to B. burgdorferi caused an increase in the production of IL-6, TNF-α, IL-8, chemokine (C-X-C motif) ligand 1 (CXCL-1), and CXCL-10 in human cultured astrocytes (Brissette et al ., 2013). …”

Neuroglia in Infectious Brain Diseases

“…Their functions include: maintaining ion and pH homeostasis, promoting synthesis and removal of neurotransmitters, providing glucose supply and antioxidant defense, and regulating synaptic activity by producing cytokines, chemokines, growth factors, and metabolites (Choi et al, 2014;Kang et al, 2014). They also assist in tight junction formation and expression and localization of transporters (Brissette et al, 2013). They also assist in tight junction formation and expression and localization of transporters (Brissette et al, 2013).…”

“…Borrelia burgdorferi is the causative agent of Lyme disease, which includes meningitis among its later manifestions in 10-15% of patients (Brissette et al, 2013;Halperin, 2014). Unlike most gram-negative bacteria, B. burgdorferi does not produce LPS, which renders it immunologically distinct from other gram-negative organisms, interacting primarily via TLR 2 rather than TLR4 (Rasley et al, 2002(Rasley et al, , 2006.…”

“…When incubated with astrocytes, B. burgdorferi has been shown to up-regulate matrix metalloprotease 9 (MMP-9) which may play a role in breaking down the blood brain barrier (Perides et al, 1999). Further studies have demonstrated an increase in IL-6, TNF-α, IL-8, CXCL-1, and CXCL-10 production by human astrocytes following exposure to B. burgdorferi, suggesting that astrocytes play a key role in recruiting phagocytes and T-lymphocytes to the CNS in Lyme meningitis (Brissette et al, 2013). These responses are at least partially dependent upon up-regulation of NOD2, as has been described previously in pneumococcus and meningococcus as noted above (Chauhan et al, 2009).…”