PATHOGENESIS OF LYME NEUROBORRELIOSIS: STUDIES EX VIVO & IN VIVO

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 莱姆氏疏螺旋体病(LNB)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，在接触莱姆病病剂伯氏疏螺旋体后，胶质细胞会产生炎性介质，促进早期莱姆氏疏螺旋体病的急性细胞渗透。这种炎性环境可以增强中枢和外周神经系统(PNS)中的神经胶质细胞和神经元的凋亡。将伯氏杆菌活菌接种于恒河猴枕大池，观察其对中枢神经系统(CNS)、背根神经和神经节(DRG、PNS)的炎症反应。脑脊液中IL-6、IL-8、CCL2和CXCL13最早在接种后一周升高，并伴有淋巴细胞和单核细胞增多。脑脊液细胞球和中枢神经系统组织培养伯氏杆菌阳性。组织病理学显示急性LNB的征象：严重的多灶性软脑膜炎、神经根炎和DRG炎性病变。重要的是，感染动物的背根神经节显示出明显的卫星细胞和神经元凋亡。根据这些结果，我们以同样的方式接种了另外5只动物，并进行了周围神经传导研究。如果DRG神经元在活体内因凋亡而死亡，我们预计会看到感觉神经传导特性的变化。此外，如果炎症参与了导致细胞凋亡，用抗炎药物地塞米松治疗一些动物可能会抑制神经传导特性的变化。

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.