Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/20104
標題: 日本腦炎病毒感染活化神經膠細胞之研究
Infection of Japanese encephalitis virus induces glial activation
作者: 陳仕昀
Chen, Shih-yun
關鍵字: Japanese encephalitis virus;日本腦炎病毒;neuroglia;cytokines;glutamate;神經膠細胞;細胞激素;麩胺酸
出版社: 生物醫學研究所
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摘要: 
日本腦炎病毒是引起日本腦炎的致病因,分類上屬於黃病毒科(Flaviviridae)黃病毒屬(Flavivirus)。日本腦炎病毒藉由蚊子叮咬進入寄主體內,臨床病例發現患者主要有神經症狀而感染侵犯部位則是中樞神經系統。感染部位的組織病理變化方面也發現,感染區的神經細胞有功能失常及死亡現象,並伴隨有顯著的發炎反應,免疫細胞浸潤。以往研究發現,有些病毒會引起一些神經退化性疾病,比如Human Immunodeficiency Virus, HIV所引起的痴呆(Dementia),HIV不會感染神經元細胞,但會感染活化神經膠細胞,促使神經膠細胞釋放神經傷害物質,造成神經元細胞死亡。此一間接傷害模式在黃病毒屬研究資料尚少。近來有文獻顯示,日本腦炎病毒感染活體動物的組織切片,可以觀察到神經膠細胞有活化的現象。因此我們的研究重點擺在日本腦炎病毒感染活化神經膠細胞的探討。在我們的研究發現,日本腦炎病毒確實會感染神經膠細胞,而且會促使被感染的神經膠細胞型態改變,也會促使細胞產生一氧化氮以及細胞激素/趨化激素(IL-1β, IL-6, TNF-α, RANTES),並且會促進微神經膠細胞增生。臨床上日本腦炎患者會出現痙攣、肌強直、異常行為等症狀近似興奮性神經毒性。神經傳導因子麩胺酸(Glutamate)的釋放會誘發鈣離子移動,造成興奮性神經毒性。在我們的研究,日本腦炎病毒確實會促使微神經膠細胞增加麩胺酸的釋放。藉由麩胺酸轉運體(Glutamate transpoter)活性抑制劑(PDC,DL-TBOA)的應用來分析堆積的原因,發現日本腦炎病毒所引起的麩胺酸釋放,並非是透過麩胺酸轉運體這一類通道。另外我們的研究也發現,麩胺酸在細胞內的產量也會因日本腦炎病毒感染而增加。而細胞內麩胺酸量增加的原因,我們證實主因是日本腦炎病毒促進麩醯胺酸酶(Glutaminase)的表現,致使細胞內麩胺酸產量增加。參考文獻,以脂多醣體(LPS)刺激微神經細胞造成麩胺酸大量釋放的模式中,其最主要的原因是TNF-α引起的。我們的研究證明,日本腦炎病毒所造成的麩胺酸釋放,TNF-α確實有參與部分調控,但並非全由TNF-α造成。我們證實另外還有一氧化氮,但不是PGE2有參與調控日本腦炎病毒感染微神經膠細胞造成的麩胺酸釋放。我們更進一步發現訊號傳遞分子PKC也有參與其中。以上,日本腦炎病毒感染活化現象所產生的發炎因子以及麩胺酸的釋放皆很有可能會間接造成神經傷害。

Japanese encephalitis virus (JEV), a member of the family Flaviviridae, which causes acute encephalitis in human. JEV targets the CNS, clinically manifesting with fever, headache, vomiting, signs of meningeal irritation, and altered consciousness, leading to high mortality and neurological sequelae in some of those who survive. Though neurological disorder caused by conventional viruses are often characterized by evidence of immune system recognition and the presence of inflammatory components among the neuropathological changes, the mechanisms by which these viruses cause neurological disease are not fully understood. In many cases, the virus is probably not directly involved in the destruction of brain tissue but many cause damage indirectly by triggering cell mediated immune response by activating glial cells. In our studies, morphological change and pro-inflammatory cytokine production were found in JEV-infected glial cells. In addition, JEV-infected microglia significantly elevated extracellular level of glutamate, a major excitotoxic neurotransmitter in the CNS. We have demonstrated that TNF-α, NO and PKC might involve in regulating glutamate release. JEV-infected microglia elevated intracellular glutamate level through the up-regulating glutaminase. Generally, cytokine production and glutamate release are well recognized events in glial activation. Our findings suggest that JEV infection induces glial activation. In conclusion, the relationship of JEV infection, neuroglia activation, and inflammatory responses are highly relative. The inflammatory responses of activated neuroglia might play a role in JEV-induced neurotoxicity.
URI: http://hdl.handle.net/11455/20104
其他識別: U0005-1708200710385800
Appears in Collections:生物醫學研究所

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