Parechovirus A3 (PeV-A3)感染在嬰幼兒會引起中樞神經系統或敗血症，然而，我們對於 PeV-A3 腦炎之致病機制仍不清楚。因此，為 了瞭解 PeV-A3 對於中樞神經系統的影響，本研究利用神經膠質瘤母細胞 和神經母細胞瘤進行 PeV-A3 感染實驗，並以 C57BL/6 新生小鼠建立 PeV- A3 感染疾病模式進行探討。我們首先評估不同營養成分的培養基所培養 的神經膠質瘤母細胞對 PeV-A3 的感受性，我們比較了胎牛血清與其替代 物—人類血小板萃取物對病毒複製的效率，我們發現人類血小板萃取物 會抑制 PeV-A3 複製能力，胎牛血清則無此現象，其原因可能是人類血小 板萃取物活化了神經膠質母細胞瘤細胞的第一型干擾素之抗病毒機制所 導致，顯示人類血小板萃取物不適合用於病毒的細胞感染實驗。因此，我們仍以常用的胎牛血清作細胞培養的培養基營養添加物進行 PeV-A3 的 研究。 我們的細胞感染研究結果顯示，PeV-A3 感染導致細胞病變並啟動 細胞死亡的訊息機轉，如細胞凋亡、細胞自噬和細胞焦亡;此外，PeV-A3 感染亦誘發神經細胞焦亡相關發炎因子之表現。進一步分析 PeV-A3 經由 顱內注射於 C57BL/6 新生鼠的感染動物，結果顯示，PeV-A3 感染的新生 鼠體重減輕、後肢癱瘓，導致約 20% 死亡率。組織學分析證明受感染之小鼠大腦海馬迴以及皮質區域可偵測到 PeV-A3，小鼠腦組織亦可測得病 毒所誘發之細胞發炎因子以及細胞死亡的相關機制，此動物實驗的發現 呼應神經細胞感染模式之結果。綜上所述，我們的研究成果證明 PeV-A3 導致了中樞神經系統性疾病，並且活化了細胞死亡信息和發炎反應，而這 些研究結果或許能解釋 PeV-A3 的臨床病徵。

Human parechovirus type 3 ( PeV-A3 ) infection has been recognized as an emerging etiologic factor causing severe nerve disease or sepsis in infants and young children. But the neuropathogenic mechanisms of PeV-A3 remain unknown. To understand the pathogenesis of PeV-A3 infection in neuronal system, PeV-A3-mediated cytopathic effects were analyzed in human glioblastoma cells and neuroblastoma cells. We first evaluated the PeV-A3 susceptibility of glioblastoma in media with different nutrients. Fetal bovine serum (FBS) and its substitute, human platelet lysate (hPL), on viral replication were compared. The result showed that hPL but not FBS inhibited the PeV-A3 replication in glioblastoma cells, this effect might due to the activation of type I interferon response by hPL in glioblastoma cells. Therefore, hPL is not suitable for cell-based viral infection experiments. Thus, the commonly used FBS was added as the medium nutrient supplement for cell culture for PeV-A3 research. In the PeV-A3-infected glioblastoma cells and neuroblastoma cells, the pronounced cytopathic effects (CPE) accompanied with activation of death signaling pathways of apoptosis, autophagy and pyroptosis were detected. A newly experimental disease model of parechovirus encephalitis was established. In the disease model, intracranial inoculation with PeV-A3 in C57BL/6 neonatal mice showed body weight loss, hindlimb paralysis and approximately 20% mortality. PeV-A3 infection in hippocampus and cortex regions of the neonatal mice brain was revealed. Mechanistic assay supported the in vitro results, indicating detection of PeV-A3 replication, inflammatory cytokines expression and death signaling transduction in mice brain tissues. These in vitro and in vivo studies revealed that the activation of death signals and inflammation responses were involved in PeV-A3-mediated neurological disorders. The present results might account for some of the PeV- A3-associated clinical manifestations. The results also implicated that hPL may be a potential antiviral bioreagent. It would be carefully evaluated the antiviral response while using commercial hPL as a FBS substitute for cell culture-based viral infection.

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