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系統識別號 U0026-3007201515044300
論文名稱(中文) 探討激肽釋放酶-1、激肽釋放酶抑制蛋白和血管內皮生長因子在流行性感冒病毒感染的角色
論文名稱(英文) Roles of kallikrein-related peptidase 1, kallistatin and vascular endothelial growth factor in influenza virus infection
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 103
學期 2
出版年 104
研究生(中文) 呂佳馨
研究生(英文) Chia-Hsing Leu
學號 s58981303
學位類別 博士
語文別 英文
論文頁數 84頁
口試委員 指導教授-吳昭良
口試委員-蕭璦莉
口試委員-王憲威
口試委員-張堯
口試委員-王金和
口試委員-朱純燕
中文關鍵字 流行性感冒病毒  血球凝集素  激肽釋放酶  激肽釋放酶抑制蛋白  血管內皮生長因子  干擾素 
英文關鍵字 influenza virus  hemagglutinin  KLK1  kallikrein  kallistatin  VEGF  interferon 
學科別分類
中文摘要 流行性感冒病毒感染是種常見的人類呼吸道疾病。流行性感冒病毒會引起發炎反應,嚴重則會導致呼吸衰竭和組織受損。流行性感冒病毒可經由抗原變異,造成病毒能躲避宿主的免疫反應並能對流感病毒的M2蛋白或是神經胺酸酶抑制所開發的抗流感藥物產生抗藥性。目前仍付出相當大的努力於發展新型的抗流感病毒藥物。流感病毒的感染需要血球凝集素(hemagglutinin)的切割,而血球凝集素通常是由宿主的類胰島素蛋白酶(trypsin-like protease)切割。激肽釋放酶-1(kallikrein-related peptidase 1,KLK1,也稱為 tissue kallikrein)是一種廣泛存在人體組織中的絲氨酸蛋白酶(serine protease)。而激肽釋放酶抑制蛋白(kallistatin)是一種絲氨酸蛋白酶抑制劑 (serine protease inhibitor) 主要由肝臟分泌,然後快速進入血液循環系統,會與激肽釋放酶-1形成複合物,進而抑制激肽釋放酶-1的活性。在本文第一部分,我們將探討激肽釋放酶-1和激肽釋放酶抑制蛋白在流行性感冒病毒的感染中所扮演的角色。我們指出激肽釋放酶-1和激肽釋放酶抑制蛋白在血球凝集素蛋白切割和發炎反應的影響,會改變流行性感冒病毒的病理現象。我們發現在流行性感冒病毒感染的小鼠肺部中,激肽釋放酶-1和激肽釋放酶抑制蛋白的表現量失衡。激肽釋放酶-1會切割流感病毒的血球凝集素並增加流感病毒的製造。相反地,激肽釋放酶抑制蛋白可藉由抑制激肽釋放酶-1的活性來降低血球凝集素蛋白的切割和流感病毒的製造。被激肽釋放酶抑制蛋白基因(kallistatin gene)所轉導(transduce)的細胞,會分泌激肽釋放酶抑制蛋白於細胞外,使細胞較能扺抗流行性感冒病毒的感染。再者,有經由激肽釋放酶抑制蛋白基因傳送後小鼠的會有較低的流感病毒量,發炎反應和肺部損傷,而降低死亡率。第二部分,我們將確認血管內皮生長因子(vascular endothelial growth factor, VEGF)在流行性感冒病毒致病機轉所扮演的角色。我們指出流感病毒的感染會抑制血管內皮生長因子的生成。流感病毒的感染會降低小鼠初生的肺纖維母細胞和正常人類肺支氣管上皮細胞株(NL-20)的血管內皮生長因子表現,但卻不會降低在第一型干擾素(interferon, IFN)缺陷的細胞(Vero cells) 的血管內皮生長因子表現。此外,我們顯示在正常人類肺支氣管上皮細胞株的實驗中聚肌苷酸胞嘧啶核苷酸[Poly(I:C)]和干擾素(IFN-α)會抑制血管內皮生長因子的表現量。當我們在人類肺支氣管上皮細胞株增加外生型血管內皮生長因子的蛋白或大量表現內生型血管內皮生長因子的基因,發現流感病毒的感染與製造並不會受到血管內皮生長因子的增加而有所影響。然而,在流感病毒感染中,先接種帶有激肽釋放酶抑制蛋白慢病毒(lentiviral vector encoding VEGF, LV-VEGF)的小鼠比先接種帶有綠色螢光蛋白基因(green fluorescent protein)慢病毒(LV-GFP)的小鼠,在肺部沖洗液中具有較少的單核細胞趨化蛋白(monocyte chemoattractant protein-1, MCP-1) 和較多的腫瘤壞死因子(tumor necrosis factor-α, TNF-α)的表現。綜合以上,我們提供了一個新的觀點在抗病毒的免疫反應和新的方法於流行性感冒病毒感染的治療。
英文摘要 Influenza virus infection is a common contagious respiratory illness in human. Influenza virus usually induces inflammatory responses. Sometimes, it results in serious respiratory failure and tissue injury. Influenza virus undergoes antigenic variation, enabling the virus to evade the immune response of the host and to confer resistance of currently available anti-influenza drugs which target viral M2 protein or neuraminidase. Considerable efforts are still being made to develop novel antiviral drugs for influenza virus. Proteolytic cleavage of the hemagglutinin (HA) by host trypsin-like proteases is required for influenza virus infection. Kallikrein-related peptidase 1 (KLK1, also known as tissue kallikrein) is a widely distributed serine protease in human tissues. Kallistatin, a serine protease inhibitors synthesized mainly in the liver and rapidly secreted into the blood circulation, forms complexes with KLK1 and inhibits its activity. In the first part, we investigated the roles of KLK1 and kallistatin in influenza virus infection. We showed that KLK1 and kallistatin contribute to the pathogenesis of influenza virus by affecting the cleavage of the HA peptide and inflammatory responses. We observed unbalance of KLK1 and kallistatin expression in the lung of mice during influenza infection. KLK1 cleaved HA molecules of influenza virus and consequently enhanced viral production. By contrast, kallistatin reduced HA cleavage and reduced viral production by inhibiting KLK1 ability. Cells transduced with the kallistatin gene secreted kallistatin extracellularly, which rendered them more resistant to influenza virus infection. Furthermore, mice with kallistatin gene delivery had less mortality by reducing viral load, inflammation, and injury in the lung. In the second part, we studied the role of vascular endothelial growth factor (VEGF) in influenza virus pathogenesis. We found that VEGF production was attenuated by influenza virus infection. Influenza virus infection decreased VEGF expression in mouse primary lung fibroblasts and normal bronchial epithelial cells (NL-20 cells), but not in type I interferon (IFN) deficient cells (Vero cells). Moreover, we showed that Poly(I:C) and IFN-α inhibited VEGF production in NL-20 cells. When we exogenously added VEGF protein or endogenously overexpressed VEGF gene in NL-20 cells, VEGF increase did not influence influenza virus infection and production. However, mice pretreated with lentiviral vectors encoding VEGF (LV-VEGF) had less monocyte chemoattractant protein-1 (MCP-1) and more tumor necrosis factor-α (TNF-α) production in bronchoalveolar lavage fluid, compared with mice pretreated with lentiviral vectors encoding green fluorescent protein (LV-GFP) during influenza infection. Collectively, we provide a novel insight in antiviral immune response and a new approach in therapy of influenza virus infection.
論文目次 Qualified Certificate I
Chinese Abstract II
Abstract IV
Acknowlegements VI
Abbreviations X
Introduction 1
Part 1: Kallistatin Ameliorates Influenza Virus Pathogenesis by Inhibition of Kallikrein-Related Peptidase 1-Mediated Cleavage of Viral Hemagglutinin 7
1.1 Abstract 7
1.2 Introduction 8
1.3 Materials and Methods 11
1.3.1 Materials 11
1.3.2 Methods 12
1.4 Results 19
1.4.1 KLK1 expression is increased, whereas kallistatin expression is reduced in mice during acute influenza virus infection 19
1.4.2 KLK1 cleaves HA of dominant human subtypes (H1, H2, and H3) of influenza virus in the contexts of HA proteins and virus particles 19
1.4.3 Treatment with KLK1 enhances influenza virus production in vitro 20
1.4.4 Kallistatin inhibits HA cleavage and reduces influenza virus production in vitro 21
1.4.5 Cells transduced with the kallistatin gene are more resistant to influenza virus infection 22
1.4.6 Treatment with lentiviral vectors expressing kallistatin protects mice against lethal influenza virus challenge and alleviates lung inflammation 22
1.5 Discussion 24
Part 2: Role of vascular endothelial growth factor in anti-influenza virus responses 30
2.1 Abstract 30
2.2 Introduction 31
2.3 Materials and Methods 34
2.3.1 Materials 34
2.3.2 Methods 35
2.4 Results 40
2.4.1 VEGF protein expression is reduced in mice infected with influenza virus 40
2.4.2 Levels of VEGF are decreased in influenza virus-infected cells 40
2.4.3 Type I IFN receptor signaling suppresses VEGF expression 41
2.4.4 Effect of VEGF on influenza virus infection and production 42
2.4.5 LV-VEGF pretreatment reduces influenza symptoms of mice 42
2.5 Discussion 44
Conclusion 48
References 49
Figure Legends 61
Appendix 82
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