臺灣博碩士論文加值系統

許多研究發現，宿主細胞中氧化壓力的狀態會影響病毒對細胞的感染能力及可能改變病毒的毒性。已證實葡萄糖-6磷酸鹽去氫酶 (G6PD)缺乏的人類纖維母細胞 (HFF)較正常細胞承受較高氧化壓力。本實驗利用G6PD缺乏細胞作為高氧化壓力之模型，探討腸病毒71型 (enterovirus71； EV71)對其的感染敏感性。G6PD缺乏細胞 (HFF1)與正常細胞 (HFF3)於病毒感染後皆呈現細胞病變效應 (cytopathic effect；CPE)。以1.25 M.O.I.病毒感染48小時後，HFF1與HFF3之細胞存活率相對於未感染者為32.4 ± 10.0 %與50.6 ± 10.4 %；產生之病毒顆粒則為2.16 ± 0.31 × 105及9.0 ± 2.8 × 104。同時於HFF1中也可發現較高的病毒蛋白表現以及基因複製倍率。若外送G6PD基因至HFF1使G6PD活性大量表現，則可明顯減緩病毒誘發之細胞死亡及病毒繁殖。另一方面，病毒感染造成細胞中活性氧增加以及GSH/GSSG比值降低，並具有隨病毒M.O.I.增加而改變之趨勢 (dose-dependent)；而抗氧化劑兒茶素 (Epigallocatechin gallate ；EGCG)或清香木 (Pistacia weinmannifolia ；PW)，可提高病毒感染後之細胞存活率；EGCG並可抑制病毒顆粒形成及病毒基因的表現程度。綜合來說， G6PD缺乏之人類纖維母細胞，對腸病毒71型感染具有較高敏感性，且EGCG可有效調降此一現象。

Accumulating evidence suggests that cellular redox status plays an important role in regulating viral replication and infectivity. Glucose 6-phosphate dehydrogenase (G6PD) deficient fibroblast has been shown to suffer higher oxidative stress than normal control part. Experiments were performed to compare the susceptibility of normal (HFF3) and G6PD-deficient (HFF1) cells to enterovirus71 (EV71) infection. After EV71 infection, both types of cells developed cytopathic effect. G6PD deficiency cells to predispose cell death in response to EV71 infection : cell viability of HFF1 was 32.4 ± 10.0 % of uninfected control whereas the viability of HFF3 was 50.6 ± 10.4 % of uninfected control .The level of progeny virus from HFF1 (2.16 ± 0.31 × 105) was 2 fold higher than that of HFF3 (9.0 ± 2.8 × 104) at 1.25 M.O.I. 48h post-infection. This data consistent with the increased expression of viral protein and increased copy number of viral genomic RNA in HFF1. In addition, ectopic expression of G6PD in the deficient cells increased their viability upon viral infection, this was associated with reduced viral replication. Furthermore, virus infection caused gradient reduction in the ratio of the level of GSH/GSSG in both type of cells. Moreover, pre-treatment antioxidant, such as Epigallocatechin gallate (EGCG) or Pistacia weinmannifolia (PW), was able to increase cell viability and inhibit viral replication in both types of cells following EV71 infection. Taken together, these data support our hypothesis that G6PD-deficient cells are highly susceptible to EV71 infection and EGCG pre-treatment can reduce the toxicity upon EV71 infection.

第一章 序論 1
1.1 研究背景 1
1.1.1 葡萄糖-6磷酸鹽去氫酶 1
1.1.2 腸病毒71型 3
1.1.3 氧化壓力與病毒感染力及毒性間的關聯 6
1.2 計畫目標 10
第二章 材料與方法 11
2.1 實驗材料 11
2.1.1 細胞株 11
2.1.2 腸病毒71型 11
2.1.3 緩衝液與試劑 12
2.2 實驗方法 11
2.2.1 細胞培養 14
2.2.2 病毒增生 15
2.2.3 病毒斑定量 15
2.2.4 MTT assay測定細胞存活率 16
2.2.5 蛋白質萃取及定量 17
2.2.6 G6PD活性測定 18
2.2.7 細胞病變效應 18
2.2.8 免疫螢光染色 19
2.2.9 活性氧物質測定 19
2.2.10 Real-time PCR定量病毒基因表現 20
2.2.11 HPLC法分析GSH/GSSG 21
2.2.12 抗氧化劑對細胞存活率影響 21
2.3 數據分析方法 22
第三章 結果 24
3.1 G6PD缺乏影響人類纖維母細胞對腸病毒71型感染的敏感性 24
3.1.1 腸病毒71型引發細胞病變效應 24
3.1.2 免疫螢光染色觀察腸病毒對細胞的影響 25
3.1.3 病毒感染降低G6PD缺乏細胞之細胞存活度 25
3.1.4 G6PD缺乏細胞可產生較多病毒顆粒 26
3.1.5 腸病毒71型3C基因表現量增加 27
3.1.6 高度表現G6PD活性可降低病毒對細胞的毒性 28
3.1.7 高度表現G6PD活性可降低病毒顆粒的形成 29
3.2 腸病毒71型感染與氧化壓力間之相關性 30
3.2.1 病毒感染後增加細胞活性氧程度 30
3.2.2 細胞受病毒感染後降低GSH/GSSG 比值 31
3.2.3 特定抗氧化劑可有效降低病毒毒性 32
3.2.4 抗氧化劑EGCG降低病毒的形成 33
第四章 討論 34
參考文獻 43
圖表 56
附錄 78

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96. 趙元章，「第二型登革熱病毒在G6PD缺乏病人單核球體外感
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