Disrupted glutamate transporter expression in the spinal cord with acute flaccid paralysis caused by West Nile virus infection.
Disrupted glutamate transporter expression in the spinal cord with acute flaccid paralysis caused by West Nile virus infection.
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DOI：
10.1097/nen.0b013e3181b8ba14
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发表时间：
2009-10
影响因子：
3.2
通讯作者：
Irani DN
中科院分区：
文献类型：
--
作者：
Blakely PK;Kleinschmidt-DeMasters BK;Tyler KL;Irani DN
神经侵袭性西尼罗河病毒(WNV)感染可导致急性弛缓性麻痹(AFP)；在致命病例中，前角细胞(AHC)丢失被推定为直接病毒感染所致。然而，在相关的动物模型中，谷氨酸的兴奋性介导了未感染的AHC的旁观者损伤，提示了其他的致病机制。我们用免疫组织化学方法检测了人WNV AFP患者脊髓和WNV AFP金黄地鼠脊髓中星形胶质细胞的主要兴奋性氨基酸转运体(EAAT)(即人的EAAT2，仓鼠的谷氨酸转运体-1)的表达。检测胶质纤维酸性蛋白(GFAP)、突触和树突状细胞标志物(即突触素、微管相关蛋白-2[MAP2])、免疫激活(HLADR)和病毒抗原。与对照组相比，患有西尼罗河病毒诱导的AFP的人和仓鼠的脊髓灰质EAAT表达减少，尽管GFAP阳性的星形胶质细胞数量更多。EAAT表达减弱的区域显示突触和树突蛋白表达减少，局部炎症明显，但感染神经元很少。这些发现表明，WNV感染导致脊髓内的局部免疫激活，进而导致星形胶质细胞谷氨酸重摄取失败，即使星形胶质细胞的数量增加；细胞外谷氨酸水平的上升可能导致感染和未感染的AHC的兴奋性毒性损伤。这种日益常见的疾病的发病机制可能涉及免疫反应和兴奋毒性机制，这些机制是潜在的治疗靶点。
Neuroinvasive West Nile virus (WNV) infections may cause acute flaccid paralysis (AFP); in fatal cases anterior horn cell (AHC) loss is presumed to be a due to direct viral infection. In related animal models, however, glutamate excitoxicity mediates bystander injury of uninfected AHCs, suggesting additional pathogenetic mechanisms. We examined expression of the principal excitatory amino acid transporter (EAAT) of astrocytes (i.e. EAAT2 in humans, glutamate transporter-1 in hamsters) in the spinal cord of human WNV AFP patients and in hamsters with WNV AFP by immunohistochemistry. Glial fibrillary acidic protein (GFAP), synaptic and dendritic markers (i.e. synaptophysin, microtubule-associated protein-2 [MAP2]), immune activation (HLA-DR), and viral antigens were also evaluated. Humans and hamsters with WNV-induced AFP had decreased spinal grey matter EAAT expression despite greater numbers of GFAP-positive astrocytes compared to controls. Areas of diminished EAAT expression showed reduced synaptic and dendritic protein expression and prominent local inflammation but few infected neurons. These findings suggest that WNV infection results in local immune activation within the spinal cord that in turn causes a failure of astrocyte glutamate reuptake even as the number of astrocytes increases; rising extracellular glutamate levels may then drive excitotoxic injury of both infected and uninfected AHCs. The pathogenesis of this increasingly common disorder likely involves immune response and excitotoxicity mechanisms that are potential therapeutic targets.