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系統識別號 U0026-2108201216281800
論文名稱(中文) 腸病毒71型操控第一型干擾素及發炎性細胞激素的反應
論文名稱(英文) Modification of the type I interferon and proinflammatory cytokine responses by enterovirus 71
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 100
學期 2
出版年 101
研究生(中文) 李一平
研究生(英文) Yi-Ping Lee
電子信箱 yipinglee@hotmail.com
學號 S58931358
學位類別 博士
語文別 英文
論文頁數 113頁
口試委員 指導教授-余俊強
召集委員-葉才明
口試委員-劉清泉
口試委員-凌斌
口試委員-廖經倫
口試委員-張堯
中文關鍵字 腸病毒71型  第一型干擾素  發炎性細胞激素 
英文關鍵字 Enterovirus 71  Type I interferon  Proinflammatory cytokine 
學科別分類
中文摘要 腸病毒71型 (EV71)是一種具神經侵犯性的病毒,好於侵襲腦幹,感染後可能引起嚴重的併發症,例如:癱瘓、肺水腫等。第一型干擾素反應是一種先天性免疫的防禦機制能夠限制病毒感染的初期步驟並阻止病毒的擴散。發炎性細胞素 (proinflammatory cytokine)則可能參與病毒感染引起的免疫致病機轉或調控宿主對抗病毒的免疫反應。在先前的研究中我們發現在感染後給予具有抗發炎作用的皮質類固醇藥物:dexamethasone,會使病毒感染所引起的臨床症狀明顯惡化並增加小鼠組織內的病毒量。而給予有效的干擾素誘發劑:人工合成雙股RNA [polyriboinosic:polyribocytidylic acid, poly (I:C)],則可以增加EV71感染小鼠存活率並降低組織內的病毒量,這個結果與血清內甲型干擾素 (interferon-α, IFN-α)濃度、脾臟內樹狀宊細胞的比例及細胞所表現的第二型組織相容性複合體與IFN-的增加有相關性。此外,給予小鼠第一型干擾素中和性抗體,會造成感染小鼠產生高致死率及高組織病毒量的現象。在本研究中, 我們更進一步地利用小鼠模式來評估第一型干擾素與發炎性細胞素在EV71感染疾病中所扮演的角色。在感染初期給予重組小鼠IFN-αA治療,可以保護小鼠對抗EV71感染。另外,在In vitro對三株人類細胞株的試驗中,人類第一型干擾素對於EV71感染所引起的細胞死亡具有直接的保護能力。然而,絕大多數的病毒為了生存競爭,會透過演化,發展出破壞第一型干擾素系統的機制。根據我們的觀察,小鼠接種EV71後所誘發的第一型干擾素的量,遠低於接種poly (I:C)、腺病毒第五型、或克沙奇病毒B3 (coxsackievirus B3, CB3)後所誘發的量。然而,EV71的感染卻可顯著地引發小鼠血清及腦中的介白質-6 (interleukin-6, IL-6)、單核球化學趨化蛋白-1 (monocyte chemoattractant protein-1, MCP-1)、腫瘤壞死因子(tumor necrosis factor, TNF)、以及丙型干擾素(interferon-γ, IFN-γ)的產生。在小鼠模式下,EV71的感染可以有效廢止poly (I:C)以及CB3誘導的第一型干擾素產生現象,但這樣的效應不發生在其他型的腸病毒感染的情況,CA24、CB2、CB3、以及echovirus 9感染小鼠後,poly (I:C)的接種仍可有效誘發小鼠產生第一型干擾素。此外,受到EV71感染的RAW264.7細胞比起未受感染的細胞,其接受poly (I:C)刺激後誘發第一型干擾素產生的能力會明顯受到抑制。我們更進一步地使用過量表現的系統在RAW264.7及成鼠的研究平台證實EV71抑制第一型干擾素的產生是透過病毒的3C蛋白所達成。然而,3C蛋白的過量表現,並不影響poly (I:C)所誘導的發炎性細胞素產生。臨床的研究指出,感染引起的發炎反應伴隨毒性發炎性細胞激素的產生可能參與EV71的致病機轉,特別是肺水腫的引發。在本研究中,小鼠感染EV71後僅誘發血清中的IL-6、IL-13以及IFN-γ少量且短暫的增加。因此,缺乏足夠量的肺水腫相關性細胞激素IL-6、IL-13以及IFN-γ參與,可能是導致無法在動物模式中觀察到EV71感染小鼠產生肺水腫的病徵的原因。實驗結果顯示:EV71感染小鼠給予IL-6, IL-13與IFN-γ細胞激素刺激後可誘發小鼠產生肺水腫與嚴重肺氣腫症狀,其嚴重程度遠大於EV71感染但未給予細胞激素刺激的組別。我們的研究證實了第一型干擾素在控制EV71感染上扮演非常重要的角色並首度揭露EV71逃脫宿主免疫攻擊的機制:EV71可以透過病毒的3C蛋白抑制宿主第一型干擾素合成,進而干擾先天性免疫防禦機制;另一方面,藉由增強發炎性細胞激素反應而導致肺水腫病程加劇。
英文摘要 Enterovirus 71 (EV71) is a neurotropic virus targeting the brain stem that may result in severe sequelae including paralysis and pulmonary edema (PE). Type I interferon (IFN) response is one of the natural immune mechanisms that can restrict early stages of viral infection and delay spread of virus. Proinflammatory cytokine may play an important role in immunopathogenesis of viral infection or regulate the host anti-viral immune responses. Previous study in our laboratory demonstrated that post-infection treatment of dexamethasone exacerbated the clinical symptom and increased the tissue viral titer, on the other hand, polyriboinosic:polyribocytidylic acid [poly (I:C)], a potent IFN inducer, improved the survival rate and decreased the tissue viral titers after EV71 challenge, which was correlated with an increase in serum IFN-α concentration, the percentage of dendritic cells, their expression of MHC class II molecule and IFN-α in spleen. In addition, treatment with a neutralizing antibody for type I IFNs resulted in frequent deaths and higher tissue viral load in infected mice as compared to control mice. In this study, the role of the type I IFN and proinflammatory cytokine responses on the disease development and process were investigated by using a murine model. Interestingly, the administration of recombinant IFN-αA immediately after EV71 infection reduced the clinical symptoms and prevented death. Furthermore, in vitro analysis of virus-induced death in three human cell lines showed that human type I IFNs exerted a direct protective effect on EV71. For counterattack, most viruses, however, have evolved a strategy for disrupting the type I IFN system. We observed that mice inoculated with EV71 produced a significantly lower amount of type I IFNs than those inoculated with poly (I:C), adenovirus type V, or coxsackievirus B3 (CB3). EV71 infection, however, mounted a proinflammatory response with a significant increase in the levels of serum and brain interleukin (IL)-6, monocyte chemoattractant protein-1, tumor necrosis factor, and IFN-γ. EV71 infection abolished both poly (I:C)- and CB3-induced type I IFN production of mice. Such effect was not extended to other enteroviruses including coxsackievirus A24, B2, B3, and echovirus 9, as mice infected with these viruses retained type I IFN responsiveness upon poly (I:C) challenge. In addition, EV71-infected RAW264.7 cells produced significantly lower amount of type I IFNs than non-infected cells upon poly (I:C) stimulation. The inhibitory effect of EV71 on type I IFN production was attributed to the viral protein 3C, which was proven using over-expression systems in both mice and RAW264.7 cells. The 3C over-expression, however, did not interfere with poly (I:C)-induced proinflammatory cytokine production. Inflammatory response with induction of toxic inflammatory cytokines has been considered as an essential component of the pathogenesis of EV71, especially the development of PE. The EV71-infected mice exhibited only a subtle and transient elevation of serum IL-6, IL-13, and IFN-γ. Thus, the absence of PE in EV71-infected mice might be attributed to inadequate proinflammatory cytokine levels of IL-6, IL-13, and IFN-γ. The results showed that systemic administration of proinflammatory cytokines IL-6, IL-13, and IFN-γ could exacerbate pulmonary abnormalities and induce mild PE in EV71-infected mice. In conclusion, this work describes that type I IFNs play an important role in controlling EV71 infection and a viral escape strategy of EV71 in which the virus on one hand disarms the host’s antiviral innate immunity by inactivating the type I IFN system through the 3C viral protein, and on the other hand, trigger proinflammatory cytokine responses to promote PE development.
論文目次 Abstract in Chinese ------------------------------- I
Abstract in English ------------------------------- III
Acknowledgements ------------------------------- V
Contents --------------------------------------- VI
Contents of figures ------------------------------- X
Contents of tables ------------------------------- XII
Chapter 1: Introduction ------------------------------- 1
A. Enterovirus 71 ----------------------- 1
1. Virology ----------------------- 1
2. Epidemiology ----------------------- 3
3. Clinical feature --------------- 3
4. Pathogenesis ----------------------- 4
5. Laboratory diagnosis --------------- 6
6. Management ----------------------- 6
7. Animal model ----------------------- 7
B. Type I interferon ----------------------- 8
1. Classification and characteristic -- 9
2. Induction ----------------------- 9
3. Receptor and signal transduction --- 10
4. Antiviral activity --------------- 11
5. Plasmacytoid dendritic cell ------- 12
6. Clinical application --------------- 13
7. Viral evasion of interferon
responses ------------------------- 14
C. Proinflammatory cytokine --------------- 17
1. Classification and characteristic--- 17
2. Induction and regulation ------- 18
3. The relationship of proinflammatory
cytokine and EV71-related pulmonary
edema ----------------------------- 18
D. Host and virus determinants of EV71
infection ------------------------------- 20
Chapter 2: Objective and specific aims --------------- 23
Chapter 3: Materials and methods --------------- 29
A. Materials ------------------------------- 29
1. Cell lines ----------------------- 29
2. Viruses ----------------------- 29
3. Experimental animals --------------- 30
4. Primers ----------------------- 30
5. Antibodies ----------------------- 30
6. Reagents ----------------------- 31
7. Kits ------------------------------- 35
8. Consumables ----------------------- 36
9. Equipments ----------------------- 37
B. Methods ---------------------------------- 39
1. Ethical treatment of animals ------- 39
2. Cells and viruses --------------- 39
3. Plasmid construction and
transfection ----------------------- 40
4. Mouse experiments --------------- 40
5. Preparation of EV71 hyperimmune
serum ----------------------------- 42
6. Collection of cells and tissue
samples --------------------------- 42
7. Determine of tissue viral titers --- 43
8. Flow cytometry -------------------- 43
9. In vitro cytopathic effect (CPE)
protection assay ------------------ 44
10. In vitro type I IFN induction ----- 45
11. Type I IFN inhibition ------------ 45
12. Cytokine analysis --------------- 45
13. RT-PCR analysis --------------- 46
14. Western blot analysis ----------- 46
15. Measurement of wet lung weight ---- 47
16. Tissue handling --------------- 47
17. Immunostaining --------------- 47
18. Statistical analysis ------------ 48
Chapter 4: Results ----------------------------------- 49
A. Type I IFNs protected against EV71
-induced disease ------------------ 49
B. Type I interferons protect human
cell lines from EV71-induced
cytopathology in vitro ------------ 50
C. EV71 failed to induce type I IFN
production in vivo and in vitro --- 50
D. EV71 induced proinflammatory
cytokine production in mice ------- 51
E. EV71 infection abolished both
poly (I:C)- and CB3-induced type I
IFN production in vivo and in vitro- 52
F. The 3C viral protein of EV71
selectively abolished poly (I:C)
-induced type I IFN but not
proinflammatory cytokine production
in mice --------------------------- 53
G. The 3C viral protein of EV71
abolished poly (I:C)-induced type I
IFN production of RAW264.7 cells -- 54
H. Proinflammatory cytokine treatment
elevated lung weight and induced
mild pulmonary edema in EV71- but
not herpes simplex virus-infected
mice ------------------------------ 55
Chapter 5: Discussion ------------------------------- 57
References ------------------------------------------ 65
Figures ----------------------------------------------- 86
Tables ----------------------------------------------- 107
Author profile --------------------------------------- 111
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