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系統識別號 U0026-2907201114452000
論文名稱(中文) 以體外模式探討兒茶酚胺類藥物於腸病毒71型感染的作用
論文名稱(英文) In vitro study of catecholamines in enterovirus 71 infection
校院名稱 成功大學
系所名稱(中) 微生物及免疫學研究所
系所名稱(英) Department of Microbiology & Immunology
學年度 99
學期 2
出版年 100
研究生(中文) 廖郁婷
研究生(英文) Yu-Ting Liao
學號 s46981038
學位類別 碩士
語文別 中文
論文頁數 97頁
口試委員 指導教授-劉清泉
口試委員-余俊強
口試委員-王貞仁
口試委員-林貴香
中文關鍵字 腸病毒71型  自主神經系統失調  兒茶酚胺類  正腎上腺素  腎上腺素  感染率  病毒效價  介白素-6  干擾素-γ 
英文關鍵字 Enterovirus 71  autonomic nervous system dysregulation  catecholamine  norepinephrine  epinephrine  infection rate  virus titer  interleukin-6  interferon-γ 
學科別分類
中文摘要 腸病毒71型是屬於Picornaviridae的親神經性病毒,自1998年在台灣爆發大流行後,是台灣每年重點防疫的病原之一。大部分腸病毒71型的感染可能是無症狀,輕則有手足口症或疱疹性咽唊炎,當病情快速惡化時,重則會導致腦幹腦炎。在臨床上將腸病毒71型的腦幹腦炎分成三階段分別是:單純腦幹腦炎、自主神經失調和肺水腫。其中我們有興趣探討自主神經系統失調與腸病毒71型感染的關係。自主神經失調是由於腸病毒71型感染至腦幹造成腦組織破壞,使得交感神經過度活化,造成神經性表徵,例如:肌肉抽搐或顫抖等症狀。但目前對於腸病毒71型造成自主神經系統失調進而併發肺水腫之致病機轉仍不清楚。由過去文獻已知在有腦幹腦炎的病人血清/血漿中,正腎上腺素和腎上腺素含量高於正常人。而已知正腎上腺素會刺激在巨噬細胞、T細胞或B細胞表面的β2-adrenergic receptor,進而影響其活化以及細胞激素的產生。而有自主神經失調和肺水腫病人的血漿或腦脊髓液中,IL-6、IL-8、IL-10、IL-13及IFN-γ會高於單純腦幹腦炎的情況。首先由臨床檢體證實有自主神經失調或肺水腫的病人 (n = 8 ) 血漿中,正腎上腺或腎上腺素含量比單純腦幹腦炎 (n = 2) 或control (n = 18) 高。因此我們想要藉由體外模式了解兒茶酚胺類在腸病毒71型感染的角色,於是先確認A549、RD、SK-N-SH、 HL-60、THP-1、Jurkat及human PBMC皆有表現α1A-和β2-adrenergic receptors。接著為建立研究兒茶酚胺類對於腸病毒71型感染免疫細胞影響之in vitro模式,HL-60、THP-1及Jurkat會先用PMA或DMSO誘導,經過誘導的細胞感染率會比未誘導的效果好。當外給THP-1或是Jurakt高濃度的正腎上腺素 (10-3~1 μg/ml) 或腎上腺素 (10-3 μg/ml)會增強細胞的感染率。在外加正腎上腺素或腎上腺素前,使用α型或β型阻斷劑阻斷adrenergic receptors會顯著降低感染率。進一步發現正腎上腺素會增加感染後的A549、SK-N-SH及hPBMC的病毒複製,病毒效價會上升。然而在我們模式中,IL-8、IL-10及IL-13的產生不會受兒茶酚胺類物質影響,大量產生仍與病毒感染有關連。但也發現正上腎腺素會促進未感染的Jurkat分泌IFN-γ,也有加強感染後hPBMC分泌IL-6的現象。總結目前結果,我們發現正腎上腺素或腎上腺素會提升腸病毒71感染,並在A549、SK-N-SH及hPBMC也發現會加強病毒複製,至於細胞激素的部分則確認IL-6及IFN-γ的產生會受正腎上腺素所影響。因此正腎上腺素或腎上腺素在腸病毒71型感染導致自主神經失調和肺水腫之治病機轉上扮演重要的角色。
英文摘要 Enterovirus 71 (EV71) is a neurotropic virus which belongs to the family Picornaviridae. It is one of the notable pathogens in Taiwan since the outbreak in 1998. Most EV71 infections commonly result in hand, foot, and mouth disease or herpangina, some cases are associated with brainstem encephalitis (BE). The EV71 BE has been categorized into three stages including uncomplicated BE, autonomic nervous system (ANS) dysregulation, and pulmonary edema (PE) clinically. ANS dysregulation is defined by the over-activation of sympathetic system which arose from destruction of brainstem. Nowadays the neural pathogenesis of EV71 infection still remains many unsolved questions. According to the previous studies, abnormal productions of epinephrine (EP) and norepinephrine (NE) were detected in plasma/serum of patients with EV71 BE. NE stimulates the β2-adrenergic receptor expressed on macrophages, T cells, and B cells to affect cytokine production. The production of IL-6, IL-8, IL10, IL-13 and IFN-γ in patients with ANS dysreglution and PE were higher than those with uncomplicated BE. In our studies, we intended to elucidate the role of catecholamines in EV71 infection. The results showed that the concentration of norepinephrine in plasma which collected from EV71-infected patients with BE (n = 2) or ANS dysregulation and PE (n = 8) were significantly higher than those from control (n = 18). A549, RD, SK-N-SH, HL-60, THP-1, Jurkat and human PBMC expressed both α1A- and β2-adrenergic receptors in cell membrane. In order to construct a suitable model to investigate how the derivatives of catecholamine influence immune cells after EV71 infection, we treated HL-60, THP-1 and Jurkat T cells induced with DMSO or PMA and then infected them with EV71/4643 were used. The results showed that the viral infection rates of induced cells were higher than non-induced cells. After EV71 infection, viral infection rates were elevated in induced cell lines which treated with conditional concentrations of NE and EP. The α- and β-blockers reduced the infection rates which raised from treatment of NE or EP. The virus titers were elevated in EV71-infected A549, SK-N-SH and hPBMC after treatment with NE. The production of IL-8, IL-10 and IL-13 were not obviously influenced by the effect of catecholamines in our model, but still related to EV71-infection. IFN-γ were increased in non-infected Jurkat which treated with NE. NE enhanced the production of IL-6 in hPBMC which isolated from two donors. In conclusion, our studies demonstrated that norepinephrine or epinephrine enhanced the infection rates of EV71 with conditional treatment. NE increased the secretion of IL-6 in infected hPBMC and IFN-γ. All results showed that NE or EP play an important role in the pathogenesis of EV71 infection in patients with ANS dysregulation and PE.
論文目次 中文摘要I
英文摘要III
誌謝V
目錄VI
圖目錄IX
縮寫索引XI

壹、緒論1
一、腸病毒71型之介紹1
A.腸病毒的分類1
B.腸病毒71型的病毒學概論2
C.腸病毒71型的傳染機率及途徑4
D.腸病毒71型的流行病學4
E.腸病毒71型的致病機轉6
F.腸病毒71型的臨床病症7
G.腸病毒71型感染與細胞激素之間的關係8
二、腸病毒71型感染與自主神經系統10
A.兒茶酚胺類物質簡介10
B.腸病毒71型感染造成自主神經系統失調之臨床表現11
C.腸病毒71型感染造成自主神經系統失調與肺水腫之關係12
D.腸病毒71型感染造成自主神經系統失調與細胞激素之關係12
E.自主神經系統與免疫細胞的關係13
三、腸病毒71型感染對於免疫細胞及細胞激素的影響13

貳、研究動機與目的15

參、實驗材料與方法17
一、實驗材料17
A.臨床檢體17
B.病毒株17
C.細胞株18
D.藥品與試劑18
E.耗材27
二、實驗方法28
A.細胞培養28
B.病毒培養30
C.免疫細胞株活化實驗32
D.偵測細胞表面的腎上腺素受器 (adrenergic receptor) 表現33
E.腸病毒71型感染細胞之確定34
F.腸病毒71型感染細胞後的變化36
G.測定臨床檢體中正腎上腺素的含量37
三、實驗設計39
A.誘導HL-60、THP-1及Jurkat實驗39
B.測定細胞表現adrenergic receptor實驗39
C.腸病毒71型感染後外加兒茶酚胺類的in vitro及ex vivo實驗40
D.正腎上腺素對於細胞激素之影響實驗41
四、統計方法與分析軟體41

肆、結果43
一、自臨床收集檢體偵測正腎上腺素之濃度43
二、偵測細胞株是否表現腎上腺素受體43
三、腸病毒71型感染HL-60、THP-1以及Jurkat的in vitro模式44
四、腸病毒71型感染免疫細胞株並外給兒茶酚胺類物質之in vitro模式46
五、腸病毒71型感染human PBMC並外給兒茶酚胺類物質之ex vivo模.48
六、腸病毒71型感染非免疫細胞株並外給正腎上腺素對於病毒效價之影響49
七、腸病毒71型感染並外給正腎上腺素對於分泌細胞激素之影響49

伍、討論51
一、偵測細胞株是否表現腎上腺素受體51
二、腸病毒71型感染並外給兒茶酚胺類物質之in vitro及ex vivo模式51
A.兒茶酚胺類在不同濃度下對於不同細胞株增加EV71感染之現象51
B.使用α-或β-blockers能有效降低EV71感染與EV71 receptor之關係53
C.兒茶酚胺類對細胞激素產生之影響54
三、G-protein coupled receptor傳遞的訊息路徑在其中可能有影響55
四、腸病毒71型的感染與cAMP的關係55
五、腸病毒71型的感染與兒茶酚胺類間關係以及意義56
六、正腎上腺素或腎上腺素與病毒感染的關聯56

陸、結論58
柒、參考文獻59
圖69
附錄89
作者簡歷97
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