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: 8358068
• 负责人: MARIO TOMAS PHILIPP
• 金额: $ 3.72万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358068
• 关键词: Acute; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Borrelia burgdorferi; CCL2 gene; CXCL13 gene; Cells; Cellular Infiltration; Cerebrospinal Fluid; Cranial nerve diseases; Dexamethasone; Encephalomyelitis; Enzyme-Linked Immunosorbent Assay; Exposure to; Funding; Ganglia; Grant; Histopathology; IL8 gene; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-6; Lesion; Life; Lyme Disease; Lyme Neuroborreliosis; Lymphocyte; Macaca mulatta; Meningitis; National Center for Research Resources; Nerve; Neural Conduction; Neuraxis; Neuroglia; Neurons; Pathogenesis; Peripheral Nerves; Peripheral Nervous System; Pharmaceutical Preparations; Pleocytosis; Primates; Principal Investigator; Property; Radiculitis; Research; Research Infrastructure; Resources; Source; Tissues; United States National Institutes of Health; afferent nerve; cisterna magna; cost; in vivo; neuron apoptosis; 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. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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 Lyme neuroborreliosis. This inflammatory context could potentiate glial and neuronal apoptosis both in the central and peripheral nervous systems (PNS). 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, PNS). 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. 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. Importantly, the DRG of infected animals showed significant satellite cell and neuronal apoptosis. On the grounds of these results we inoculated 5 additional animals in the same fashion, and are performing peripheral nerve conduction studies. If DRG neurons are dying by apoptosis in vivo we expect to see changes in sensory nerve conduction properties. Moreover, if inflammation is involved in causing apoptosis, treatment of some of the animals with the anti-inflammatory drug dexamethasone may curb the alterations in nerve conduction properties.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 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，促进早期莱姆病神经疏螺旋体病的急性细胞浸润。这种炎症环境可以增强中枢和外周神经系统（PNS）中的胶质细胞和神经元凋亡。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，PNS）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。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。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。基于这些结果，我们以相同的方式接种了另外5只动物，并进行了外周神经传导研究。如果DRG神经元在体内因凋亡而死亡，我们期望看到感觉神经传导特性的变化。此外，如果炎症参与引起细胞凋亡，用抗炎药地塞米松治疗一些动物可能会抑制神经传导特性的改变。