腸病毒71型誘發神經細胞凋亡的訊號傳遞機制及病毒的臨床檢驗基因晶片

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研究生：	陳燦麒 Tsan-Chi Chen
論文名稱：	腸病毒71型誘發神經細胞凋亡的訊號傳遞機制及病毒的臨床檢驗基因晶片 Signaling Mechanism of Enterovirus 71-Triggered Neuronal Apoptosis and Design of Clinical Diagnostic Gene Chip for Virus Detection
指導教授：	黎耀基 Yiu-Kay Lai 莊志立 Jyh-Lyh Juang
口試委員:
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生命科學系 Department of Life Sciences
論文出版年：	2007
畢業學年度：	95
語文別：	英文
論文頁數：	78
中文關鍵詞：	腸病毒71型、克沙寄病毒A16型、手足口病、中樞神經系統、神經細胞凋亡、週期素依賴性激酶第五型、小髮夾結構核醣核酸干擾、多引子反轉錄酶-聚合酶鏈反應、微陣列晶片
外文關鍵詞：	enterovirus 71 (EV71), coxsackievirus A16 (CA16), hand-foot-and-mouth disease (HFMD), central nerve system (CNS), neuronal apoptosis, cyclin-dependent kinase 5 (Cdk5), short hairpin RNAi (shRNA), multiplex RT-PCR, microarray
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腸病毒71型(Enterovirus 71)是屬於微小核醣核酸病毒科(Picornaviridae family)中之腸病毒屬(Enterovirus genus)。於過去三十年間，世界各地爆發幾個腸病毒71型的流行案例，包括巴西、保加利亞、匈牙利、日本、馬來西亞、新加坡、台灣、美國等國家。大部份感染腸病毒71型的病患，只表現輕微的臨床症狀，像是手足口病(HFMD)和咽喉炎(pharyngitis)；然而，在某些嚴重的感染病例，腸病毒71型造成急性腦膜炎(meningitis)、腦炎(encephalitis)、腦脊髓炎(encephalomyelitis)或類小兒麻痺症候群(polio-like syndrome)的臨床症狀，甚至造成死亡的病例。雖然腸病毒71型造成的神經傷害對嚴重臨床併發症的病患來說，是一個關鍵的原因，但是調控腸病毒71型引發神經細胞死亡的分子機制仍不明確。於此，我們提出一個在大腦受各種毒害神經條件下的關鍵訊號受動器－Cdk5，也在神經細胞受腸病毒71型感染之下被活化，利用抑制Cdk5激酶活性或降低蛋白質表現的方法，可以有效制止腸病毒71型所誘發神經細胞凋亡的現象；再者，腸病毒71型誘使Cdk5的活化是受到c-Abl的調控，利用STI571抑制c-Abl激酶活性，可明顯壓抑感染腸病毒71型的神經細胞內的Cdk5激酶活性及神經細胞凋亡的現象。雖然腸病毒71型也誘使非神經細胞的細胞凋亡，但在腸病毒71型感染的幾個非神經細胞株的分析，Abl和Cdk5的活性並不受任何的影響。另外，一個與腸病毒71型有著基因序列相似的腸病毒－克沙奇病毒A16型(Coxsackievirus A16)通常不造成嚴重神經機能失調，只會稍微活化Abl，但並不再進一步去活化Cdk5。據此，我們提出一個對腸病毒血清型及宿主細胞種類專一的調節神經細胞凋亡機制－腸病毒71型誘發Abl激酶活化，繼而起動Cdk5訊號，再誘使神經細胞凋亡。
儘管腸病毒71型和克沙奇病毒A16型有著緊密地遺傳關聯性，但就基本認知上，腸病毒71型是一個持續性的致病原，與嚴重臨床表徵及死亡病例有關聯。腸病毒的血清分型大部份是藉由傳統免疫學的方法分析，但因對抗腸病毒表面蛋白質具血清型專一的抗體之數量有限情況之下，導致很多臨床上的檢體之血清型無法被正確的分型。生物微晶片具有高度準確性及同時檢測多種血清型的特性，所以我們將多引子反轉錄聚合鏈反應(MRT-PCR)與腸病毒微陣列技術(microarray)結合，試圖發展一套可準確檢測並區分腸病毒71型和克沙奇病毒A16型的檢測方法。我們對取得各種不同腸病毒血清型的基因序列資料，進行詳細的生物資訊分析，以設計出對腸病毒血清型專一的探針。然後以篩選出長度為60個兼併寡核酸探針點在微陣列玻璃晶片上而建構成微陣列腸病毒檢測晶片。我們分析了144個手足口病病患或可疑病患的臨床檢體，結果顯示此檢驗晶片對腸病毒71型及克沙奇病毒A16型的檢測率分別達到92.0%及95.8%；相對地，針對其它血清型的檢測率可達到92.0%。這個高敏銳的微晶片檢測方法將是一個有效地區分腸病毒71型及克沙奇病毒A16型的另類方法。

Enterovirus 71 (EV71) belongs to the genus Enterovirus within the family Picornaviridae. In the past three decades, there are several reported EV71 outbreaks in the world, including Brazil, Bulgaria, Hungary, Japan, Malaysia, Singapore, Taiwan, and USA. Most patients infected with EV71 only exhibited mild clinical symptoms, such as hand-foot-and-mouth diseases (HFMD) and pharyngitis. However, acute meningitis, encephalitis, encephalomyelitis, polio-like syndrome, and even fatal cases might be caused by EV71 infection in some severe cases. Although the neurological damage is a critical cause for severe clinical syndromes, the underlying molecular mechanism that regulates the EV71-triggered neuronal cell death remains unclear. Herein, we show that Cdk5, a critical signaling effector of various neurotoxic insults in the brain, is activated by EV71 infection of neuronal cells. EV71-induced neuronal apoptosis could be effectively repressed by blocking either Cdk5 kinase activity or its protein expression. Moreover, EV71-induced Cdk5 activation was modulated by c-Abl. The suppression of c-Abl kinase activity by STI571 notably repressed both the Cdk5 activation and neuronal apoptosis in cells infected with EV71. Although EV71 also induces apoptosis in non-neuronal cells, it did not affect Abl and Cdk5 activities in several non-neuronal cell lines. Intriguingly, coxsackievirus A16 (CA16), a genetically closely related serotype to EV71 that usually does not induce severe neurological disorders, could only weakly stimulate Abl, but not Cdk5 kinase activity. Taken together, our data suggests a serotype- and cell type-specific mechanism, by which EV71 induces Abl kinase activity, which in turn triggers Cdk5-signaling for neuronal apoptosis.
Despite the close genetic relationship between EV71 and CA16, EV71 is generally known to be a more perpetuating pathogen involved in severe clinical manifestations and deaths. While the serotyping of enteroviruses is mostly done by conventional immunological methods, many clinical specimens remain unclassifiable due to the limited number of serotype-specific antibodies against enterovirus surface proteins. Array-based assay is able to simultaneously detect several serotypes with high accuracy. We combined an enterovirus microarray with multiplex RT-PCR (MRT-PCR) to try to develop a method of sensitively and accurately detecting and differentiating EV71 and CA16. In an effort to design serotype-specific probes for detection of the virus, we first did an elaborate bioinformatic analysis of the sequence database derived from different enterovirus serotypes. We then constructed a microarray using 60-mer degenerate oligonucleotide probes covalently bound to array glass slides. Using this enterovirus microarray to study 144 clinical specimens of HFMD or suspected cases, we found that it had a diagnostic accuracy of 92.0% for EV71 and 95.8% for CA16. Diagnostic accuracy for other enteroviruses (non-EV71 or -CA16) was 92.0%. This highly sensitive array-based assay may become a useful alternative in clinical diagnostics of EV71 and CA16.

Publications ……………………… I
Abbreviations ……………………… II
中文摘要 ……………………… 1
English abstract ……………………… 3
Chapter I: Enterovirus 71 triggering of neuronal apoptosis through activation of Abl-Cdk5 signaling ……………………… 5
Introduction ……………………… 6
Materials and Methods ……………………… 8
Results ……………………… 13
Discussions ……………………… 20
Chapter II: Combining multiplex reverse transcription-PCR and a diagnostic microarray to detect and differentiate enterovirus 71 and coxsackievirus A16 ……………………… 23
Introduction ……………………… 24
Materials and Methods ……………………… 26
Results ……………………… 31
Discussions ……………………… 37
Chapter III: Perspectives ……………………… 39
Chapter IV: Figures and Tables ……………………… 43
Figure 1.    EV71 triggers Cdk5 kinase activity and the blockage of Cdk5 activation suppresses the neuronal apoptosis ……………………… 44
Figure 1.    (Cont. 1) ……………………… 45
Figure 1.    (Cont. 2) ……………………… 46
Figure 2.    EV71 initiates Cdk5 Tyr15 phosphorylation and Abl kinase activation in neuronal cells ……………………… 47
Figure 2.    (Cont.) ……………………… 48
Figure 3.    Abl is essential for initiation of Cdk5 kinase activity and EV71-induced neuronal apoptosis ……………………… 49
Figure 3.    (Cont. 1) ……………………… 50
Figure 3.    (Cont. 2) ……………………… 51
Figure 4.    UV-irradiated EV71 also triggered Abl and Cdk5 kinase activities in neuronal cells ……………………… 52
Figure 5.    EV71 infection increased Abl and Cdk5 expression levels by post-transcriptional regulation ……………………… 53
Figure 6.    EV71 did not initiate Abl and/or Cdk5 kinase activity in non-neuronal cells ……………………… 54
Figure 6.    (Cont.) ……………………… 55
Figure 7.    CA16 was less efficient than EV71 in inducing Abl activity and incapable of activating Cdk5 in neuronal cells ……………………… 56
Figure 7.    (Cont. 1) Blockade of Abl gene expression or activation did not suppress the CA16-induced neuronal apoptosis in SH-SY5Y cells ……………………… 57
Figure 7.    (Cont. 2) ……………………… 58
Figure 8.    Western blot analysis of apoptosis-related proteins in EV71-infected SH-SY5Y cells at 6 and 24 hpi ……………………… 59
Figure 9.    Virtual screening flowchart for design of EV71-specific probes ……………………… 60
Figure 10.Sensitivity and specificity of array probes ……………………… 61
Figure 10    .(Cont. 1) ……………………… 62
Figure 10    .(Cont. 2) ……………………… 63
Figure 10.(Cont. 3) ……………………… 64
Figure 11.Combining MRT-PCR and microarray for clinical detection of EV71 and CA16 in specimens ……………………… 65
Table 1.Candidate probes and primers used for EV microarray analysis ……………………… 66
Table 2.Degenerate probes used for EV microarray analysis ……………………… 67
Table 3.Results of 144 diagnoses from HFMD-related specimens by array-based assay ……………………… 68
References ……………………… 69

                                

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