PATHOGENESIS OF LYME NEUROBORRELIOSIS: STUDIES EX VIVO & IN VIVO

莱姆病神经疏螺旋体病的发病机制：离体研究

• 批准号: 8172962
• 负责人: MARIO TOMAS PHILIPP
• 金额: $ 6.18万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172962
• 关键词: Acute; Animals; Antibodies; Antigens; Apoptosis; Astrocytes; Borrelia burgdorferi; CCL2 gene; CXCL13 gene; Cells; Cellular Infiltration; Cerebrospinal Fluid; Computer Retrieval of Information on Scientific Projects Database; Confocal Microscopy; Cranial nerve diseases; Encephalomyelitis; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Exposure to; Funding; Ganglia; Grant; Histopathology; IL8 gene; Immune response; Immunofluorescence Immunologic; Inflammation; Inflammation Mediators; Inflammatory; Institution; Interleukin-6; Lesion; Life; Lyme Disease; Lyme Neuroborreliosis; Lymphocyte; Macaca mulatta; Mediating; Meningitis; Microglia; Myxoid cyst; Nerve; Neuraxis; Neuroglia; Neurons; Pathogenesis; Pleocytosis; Radiculitis; Research; Research Personnel; Resources; Serum; Source; Spinal Cord; Staining method; Stains; T-Lymphocyte; Tissues; United States National Institutes of Health; cisterna magna; in vivo; macrophage; neuron apoptosis; response; satellite cell; spinal nerve posterior root

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Lyme neuroborreliosis (LNB) may present as meningitis, cranial neuropathy, acute radiculoneuropathy or, rarely, as encephalomyelitis. We hypothesized that glia, upon exposure to Borrelia burgdorferi, the Lyme disease agent, produce inflammatory mediators that promote the acute cellular infiltration of early LNB. This inflammatory context could potentiate glial and neuronal apoptosis. We inoculated live B. burgdorferi into the cisterna magna of rhesus macaques and examined the inflammatory changes induced in the central nervous system (CNS), and dorsal root nerves and ganglia (DRG). ELISA of the cerebrospinal fluid (CSF) showed elevated IL-6, IL-8, CCL2, and CXCL13 as early as one week post-inoculation, accompanied by primarily lymphocytic and monocytic pleocytosis. In contrast, onset of the acquired immune response, evidenced by anti-B. burgdorferi C6 serum antibodies, was first detectable after 3 weeks post-inoculation. CSF cell pellets and CNS tissues were culture-positive for B. burgdorferi. Histopathology revealed signs of acute LNB: severe multifocal leptomeningitis, radiculitis, and DRG inflammatory lesions. Immunofluorescence staining and confocal microscopy detected B. burgdorferi antigen in the CNS and DRG. IL-6 was observed in astrocytes and neurons in the spinal cord, and in neurons in the DRG of infected animals. CCL2 and CXCL13 were found in microglia as well as in endothelial cells, macrophages and T cells. Importantly, the DRG of infected animals showed significant satellite cell and neuronal apoptosis. Our 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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 莱姆病可表现为脑膜炎、颅神经病、急性神经根神经病，或罕见的脑脊髓炎。我们假设，神经胶质细胞，暴露于莱姆病病原体伯氏疏螺旋体后，产生炎症介质，促进早期LNB的急性细胞浸润。这种炎症环境可以增强神经胶质细胞和神经元的凋亡。我们接种了活的B。burgdorferi的方法注入恒河猴的小脑延髓池，并检查在中枢神经系统（CNS）和背根神经和神经节（DRG）中诱导的炎症变化。早在接种后一周，脑脊液（CSF）的ELISA显示IL-6、IL-8、CCL 2和CXCL 13升高，并伴有主要淋巴细胞和单核细胞的白细胞增多。相反，获得性免疫反应的发生，由抗B。在接种后3周后首次检测到伯氏C6血清抗体。CSF细胞团和CNS组织培养物呈B阳性。burgdorferi。组织学检查显示急性LNB体征：重度多灶性软脑膜炎、神经根炎和DRG炎性病变。免疫荧光染色和共聚焦显微镜检测B。中枢神经系统和背根神经节中的伯氏抗原。在脊髓中的星形胶质细胞和神经元中以及在感染动物的DRG中的神经元中观察到IL-6。CCL 2和CXCL 13存在于小胶质细胞以及内皮细胞、巨噬细胞和T细胞中。重要的是，感染动物的DRG显示出显著的卫星细胞和神经元凋亡。我们的研究结果支持神经胶质细胞对B. burgdorferi启动/介导急性LNB中观察到的炎症，并显示在这种情况下发生神经元凋亡。