The broad, long-term objective of this proposal is to further our understanding of the pathogenesis of Lyme neuroborreliosis. We have established that live Borrelia burgdorferi spirochetes elicit inflammatory mediators from microglia and astrocytes. When B. burgdorferi penetrate brain tissue cultured ex vivo, glial cells produce inflammatory mediators and, concomitantly, oligodendrocytes and neurons undergo apoptosis. We have further determined, in rhesus macaques with Lyme meningitis due to intrathecal B. burgdorferi inoculations, that neurons and glia in dorsal root ganglia also undergo apoptosis. We have shown, moreover, that spirochetes co-cultured in vitro with neurons alone fail to elicit neuronal apoptosis but when microglia are present in the cultures neuronal apoptosis readily occurs. Astrocytes do no exert this effect. Microglia, in contrast to neurons or astrocytes, release very large amounts of inflammatory mediators when exposed to B. burgdorferi in vitro. A predominant mediator released by microglia in vitro and into the cerebrospinal fluid of rhesus macaques with Lyme meningitis is the chemokine C-C motif ligand 2 (CCL2, aka MCP-1). While these findings suggest that inflammation is required to elicit apoptosis of neurons and glial cells, a causal relationship between these two phenomena has not been demonstrated in Lyme neuroborreliosis. In addition, the mechanism whereby spirochetes activate microglia has not been examined in full. Thus far we have demonstrated that the adaptor molecule myeloid differentiation primary response gene 88 (MyD88), and the receptors Toll-like receptor 1 (TLR1), and TLR2 are directly involved in the activation of macrophage/monocytes by live B. burgdorferi, and that these TLR are expressed, and their expression is up-regulated, in primary rhesus microglia. We have also shown that MyD88 is involved in the response of microglia to B. burgdorferi. To move the field forward in the direction prescribed by these findings we propose to evaluate the following hypotheses:
Specific aim 1) inflammation is required for B. burgdorferi to cause neuronal and oligodendrocyte apoptosis.
Specific aim 2) as with neurons, microglia are necessary and sufficient as a source of the inflammatory response that causes apoptosis of oligodendrocytes.
Specific aim 3) a. the inflammatory response to live B. burgdorferi in microglia involves the TLR pathway;b. CCL2 is a key player in this process. We plan to address these goals with experiments in vitro, ex vivo, and in vivo, using the rhesus monkey model of Lyme disease.
Lyme disease, the most frequently reported arthropod-borne disease in the United States is caused by the spirochete Borrelia burgdorferi. Lyme neuroborreliosis is a form of Lyme disease that affects both the peripheral and central nervous systems, causing facial paralysis, nerve pain, sensory loss, weakness, meningitis, neurocognitive abnormalities, and loss of memory. Based on evidence collected in the preceding grant period we will address the hypothesis that inflammation brought about by the interaction between microglia, the brain phagocytic cell, and B. burgdorferi, causes Lyme neuroborreliosis by killing neurons and oligodendrocytes. This research could lead to a new way of treating Lyme neuroborreliosis.
|Parthasarathy, Geetha; Philipp, Mario T (2014) The MEK/ERK pathway is the primary conduit for Borrelia burgdorferi-induced inflammation and P53-mediated apoptosis in oligodendrocytes. Apoptosis 19:76-89|
|Ramesh, Geeta; Santana-Gould, Lenay; Inglis, Fiona M et al. (2013) The Lyme disease spirochete Borrelia burgdorferi induces inflammation and apoptosis in cells from dorsal root ganglia. J Neuroinflammation 10:88|
|Ramesh, Geeta; MacLean, Andrew G; Philipp, Mario T (2013) Cytokines and chemokines at the crossroads of neuroinflammation, neurodegeneration, and neuropathic pain. Mediators Inflamm 2013:480739|
|Parthasarathy, Geetha; Fevrier, Helene B; Philipp, Mario T (2013) Non-viable Borrelia burgdorferi induce inflammatory mediators and apoptosis in human oligodendrocytes. Neurosci Lett 556:200-3|
|Ramesh, Geeta; Benge, Shemi; Pahar, Bapi et al. (2012) A possible role for inflammation in mediating apoptosis of oligodendrocytes as induced by the Lyme disease spirochete Borrelia burgdorferi. J Neuroinflammation 9:72|
|Dennis, Vida A; Dixit, Saurabh; O'Brien, Shannon M et al. (2009) Live Borrelia burgdorferi spirochetes elicit inflammatory mediators from human monocytes via the Toll-like receptor signaling pathway. Infect Immun 77:1238-45|
|Bernardino, Andrea L F; Kaushal, Deepak; Philipp, Mario T (2009) The antibiotics doxycycline and minocycline inhibit the inflammatory responses to the Lyme disease spirochete Borrelia burgdorferi. J Infect Dis 199:1379-88|
|Ramesh, Geeta; Borda, Juan T; Gill, Amy et al. (2009) Possible role of glial cells in the onset and progression of Lyme neuroborreliosis. J Neuroinflammation 6:23|
|Myers, Tereance A; Kaushal, Deepak; Philipp, Mario T (2009) Microglia are mediators of Borrelia burgdorferi-induced apoptosis in SH-SY5Y neuronal cells. PLoS Pathog 5:e1000659|
|Myers, Tereance A; Nickerson, Cheryl A; Kaushal, Deepak et al. (2008) Closing the phenotypic gap between transformed neuronal cell lines in culture and untransformed neurons. J Neurosci Methods 174:31-41|
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