臺灣博碩士論文加值系統

腸病毒71型的感染會引發重症的中樞神經疾病，而且可能對於發育中的神經系統有所損傷，故我們希望探討腸病毒71型之感染對於小鼠神經幹細胞在生長與分化能力上的影響。我們發現受EV71 4643 MP4感染後的神經幹細胞相較於P2感染後有明顯的細胞病變，並表現細胞凋亡的標記active caspase 3。MP4在神經幹細胞中的感染效率相較於P2來說高很多，其病毒蛋白3D的表現量在感染後一天內達到高峰，之後漸漸的下降。MP4感染下的病毒效價在感染後有一次大幅的上升，之後逐漸下降；P2則沒有明顯的波動。此外，我們發現不論是神經元細胞或者星狀細胞受到感染後都沒有顯著的細胞病變，感染比例也都遠低於未分化的神經幹細胞。另一方面，我們發現受MP4感染過後的細胞，大部分已死亡但有少部分會殘存下來繼續複製生長，並且表現已分化細胞標記，我們將這些細胞稱為殘存細胞，其培養基稱為殘存培養基。這些細胞不易受到感染，且經過殘存培養基處理後的神經幹細胞可以分化為GFAP陽性的細胞，顯示殘存培養基中具有誘導神經幹細胞分化為星狀細胞的物質。MP4及P2的RNA經過轉染後皆可以在神經幹細胞內大量的表現病毒蛋白3D，顯示病毒感染比例差異可能來自於所利用的受器，如mSCARB2。但這些細胞中mSCARB2的表現量皆無差異，可能不會做為病毒感染細胞的主要受器。未來，我們會持續探討EV71在感染小鼠神經幹細胞上的機制，希望更加了解EV71與其所引起的神經性損傷之間的關係。

Enterovirus 71 (EV71) infection causes CNS involvement in children. Some of EV71-infected children who had cardiopulmonary failure after CNS involvement are found associated with neurologic sequelae, delayed neurodevelopment, and reduced cognitive functioning. However, the mechanism that EV71 infection induced neurodevelopmental deficiency is still unclear. In this study, we showed that EV71 could infect mouse neural stem cells (mNSCs) and induced apoptosis. After EV71 infection, the CPE was significantly appeared in EV71 4643 MP4-infected mNSCs than in EV71 4643 P2-infected mNSCs. EV71 could infect mNSCs and expressed viral protein 3D. Active caspase 3 also could be detected in 3D-positive shrunken cell. The expression level of 3D were abundant in 1 day postinfection. Virus titer of MP4 would increase in 12h post infection. In comparison with mNSCs, the infection percentage of EV71 in mNSCs was higher than differentiated cells. After secondary infection, survived cells had no significant CPE. IFA results showed that the infection percentages of EV71 in survived cells were much lower than in original mNSCs. The survived cells expressed nestin and GFAP, but not MAP2, showed that the cells may carry on astrocytic differentiation. GFAP also be detected in cells which treated by infected cells, demonstrated that infected medium could induce astrocytic differentiation. In addition, after transfection of MP4 and P2 RNA, we could similarily detect viral protein 3D in mNSCs, showed that different infection percentage of MP4 and P2 may caused by receptor. The expression level of mouse SCARB2 in survived cells, differentiated cells and mNSCs were similar, demonstrated that mouse SCARB2 may not be a mainly receptor during EV71 infection.

[目錄]
指導教授推薦書
口試委員會審定書
國家圖書館博碩士論文電子檔案上網授權書 iii
長庚大學博碩士論文著作授權書 iv
誌謝 v
中文摘要 vi
英文摘要 viii
縮寫對照表 x
目錄 xi
圖表目錄 xiv
第一章　前言 1
1.1 腸病毒的簡介 1
1.2 腸病毒的流行病學 2
1.3 EV71感染之動物模式 3
1.4 腸病毒及神經幹細胞的關係 4
1.5 實驗設計與研究目的 5
第二章　實驗方法與材料 6
2.1 細胞與病毒株 6
2.2 病毒增殖 6
2.3 利用EV71 4643 MP4和P2 strain感染老鼠腦神經幹細胞 7
2.4 觀察老鼠腦神經幹細胞被EV71 4643感染之後是否有CPE產生 7
2.5 抽取病毒感染後的老鼠腦神經幹細胞的細胞蛋白質 8
2.6 利用西方墨點法(western blotting)觀察EV71 4643 之3D protein表現量 8
2.7 利用免疫螢光染色法(Immunofluorence Assay；IFA)偵測nestin及EV71 4643之3D protein確認病毒感染腦神經幹細胞 10
2.8 利用plaque assay偵測EV71 4643在老鼠神經幹細胞的生長曲線 11
2.9 神經元細胞之分化及感染 13
2.10 星狀細胞之分化及感染 14
2.11利用免疫螢光染色法偵測active caspase 3及EV71 4643之3D protein確認病毒感染之後會引發細胞凋亡 15
2.12殘存培養液的製備與處理 15
2.13利用西方墨點法觀察受EV71感染後細胞mSCARB2 protein表現量 16
第三章　結果 18
3.1 小鼠神經幹細胞的特性 18
3.2 老鼠神經幹細胞經過EV71感染之後可發現明顯的細胞病變 18
3.3 受感染的老鼠神經幹細胞可以偵測到病毒蛋白3D的存在 19
3.4 EV71 4643 MP4的感染會引發神經幹細胞產生細胞凋亡 20
3.5在老鼠神經幹細胞內的生長曲線 21
3.6 EV71較易感染未分化之小鼠神經幹細胞 22
3.7 EV71感染後殘存的細胞較不易受到感染 23
3.8 殘存細胞有表現分化的標記 24
3.9 EV71感染會使小鼠神經幹細胞中的mSCARB2表現量下降 25
3.10 mSCARB2之表現量在神經幹細胞、分化後細胞以及殘存細胞中無顯著差異 26
第四章　討論 27
參考文獻 36
圖表 47

[圖表目錄]
表一、EV71在神經幹細胞、星狀細胞、神經元細胞以及殘存細胞中的感染比例 47
圖一、小鼠神經幹細胞的特性鑑定 48
圖二、小鼠腦神經幹細胞受EV71 4643 MP4感染後產生細胞病變 49
圖三、小鼠腦神經幹細胞受EV71 4643 P2感染後未產生明顯細胞病變 50
圖四、小鼠腦神經幹細胞經EV71感染後有3D及active caspase 3的表現 51
圖五、小鼠腦神經幹細胞經EV71感染後其蛋白質內可偵測到3D 53
圖六、EV71 4643在神經幹細胞內的生長曲線 54
圖七、EV71不易感染已分化之神經元細胞或星狀細胞圖 55
圖八、EV71不易感染殘存細胞 56
圖九、殘存細胞表現的細胞標記 57
圖十、殘存培養液處理後會誘導神經幹細胞進行星狀細胞的分化 58
圖十一、小鼠腦神經幹細胞經EV71感染後mSCARB2表現量會下降 59
圖十二、mSCARB2在神經幹細胞、已分化細胞以及殘存細胞中的表現 60
圖十三、MP4及P2的RNA皆可有效的在小鼠神經幹細胞中表現 61

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