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系統識別號 U0026-0407201311442200
論文名稱(中文) 缺乏內生性CXCL10加重疱疹性角膜炎和腸病毒七十一型引起小鼠腦炎之機制探討
論文名稱(英文) Absence of CXCL10 Aggravates Herpetic Stromal Keratitis and EV71-induced Encephalitis in Mice
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 101
學期 2
出版年 102
研究生(中文) 沈芳秀
研究生(英文) Fang-Hsiu Shen
學號 s58951382
學位類別 博士
語文別 英文
論文頁數 73頁
口試委員 指導教授-陳舜華
召集委員-葉才明
口試委員-彭貴春
口試委員-王憲威
口試委員-廖楓
口試委員-顧家綺
中文關鍵字 單純疱疹病毒  疱疹性角膜炎  CXCL10蛋白  腸病毒七十一型 
英文關鍵字 HSV-1  HSK  CXCL10  EV71 
學科別分類
中文摘要 單純疱疹病毒(HSV-1)在眼角膜複製引起發炎反應與血管新生,會造成疱疹性角膜炎(HSK),為臨床上常見於由感染引起視力受損的主因之ㄧ。細胞趨化素被分泌後召集白血球到感染處並限制病毒的生長,同時細胞趨化素也會影響血管新生作用而調節HSK的致病過程。我們的研究利用小鼠感染模式來探討細胞趨化素CXC chemokine ligand 10 (CXCL10; gamma interferon-inducible protein10 [IP-10])在HSK所扮演的角色。結果發現HSV-1感染小鼠的眼角膜表皮細胞可表現CXCL10蛋白。CXCL10基因缺陷鼠在感染後2至3天,眼角膜會分泌較少的IL-6與較少的第一波之嗜中性球浸潤,並且在眼球感染後有較差的病毒清除能力。在感染後14至28天,CXCL10基因缺陷鼠具有較嚴重的疾病表現,其眼角膜會分泌較多的IL-6與可召集CD4 T細胞或嗜中性球的細胞趨化素MIP-1α與MIP-2,以及血管新生因子VEGF-A和FGF-2,因此增加第二波的嗜中性球與CD4 T細胞的浸潤,最後導致眼角膜混濁與血管新生作用旺盛而使小鼠視力受損加劇。我們的研究推論,內生性的CXCL10會促進第一波的嗜中性球浸潤,調節細胞激素、細胞趨化素與血管新生因子的分泌進而降低病毒量,最後可減輕HSK的病情。
腸病毒七十一型(EV71)感染引起的致死型腦炎在近十年已造成亞太地區數千名孩童死亡。由於尚無有效的預防性疫苗與成功的抗病毒策略,因此EV71感染仍時常造成地區性的大流行。已知在EV71感染的病患與實驗小鼠的腦中可測得淋巴球的浸潤,進而降低病毒量並保護實驗小鼠。然而在病毒感染的組織中,負責調控淋巴球浸潤的細胞激素仍需進一步的研究。先前的研究已知,在EV71感染引起的腦幹腦炎病患之血清與脊髓液中發現,比起monokine induced by gamma interferon (Mig)蛋白量,較高的CXCL10蛋白可被測得。在本篇研究,我們利用實驗小鼠模式去偵測感染EV71小鼠體內CXCL10的蛋白量變化,發現CXCL10蛋白在小鼠血清與腦組織表現有明顯的上升,其上升的變化與該組織病毒量增加的趨勢相似。同時發現被感染的小鼠腦組織中,神經細胞會表現CXCL10。比較EV71感染後的野生型小鼠與CXCL10基因缺陷鼠,發現CXCL10基因缺陷鼠在血清測得較少的Mig蛋白,並在腦組織測得較少的gamma interferon蛋白和CD8 T細胞浸潤。與野生型小鼠比較後發現,缺乏CXCL10會增加45%感染小鼠的死亡率,同時其數個重要器官的病毒清除率也較慢。總結而言,EV71感染後會促進CXCL10蛋白產生,進而使gamma interferon與Mig蛋白量增加,並促進CD8 T細胞浸潤與病毒清除,最後使感染小鼠存活率增加。
英文摘要 Herpes simplex virus 1 (HSV-1) replication initiates inflammation and angiogenesis responses in the cornea to result in herpetic stromal keratitis (HSK), which is a leading cause of infection-induced vision impairment. Chemokines are secreted to modulate HSK by recruiting leukocytes which affect viral growth and by influencing angiogenesis. The present study used a murine infection model to investigate the significance of the chemokine, CXC chemokine ligand 10 (CXCL10; gamma interferon-inducible protein10 [IP-10]), in HSK. Here we show that HSV-1 infection of the cornea induced CXCL10 protein expression in epithelial cells. The corneas of mice with a targeted disruption of the gene encoding CXCL10 displayed decreases in levels of neutrophil-attracting cytokine (interleukin-6), primary neutrophil influx, and viral clearance 2 or 3 days post-infection. Subsequently, absence of CXCL10 aggravated HSK with elevated levels of interleukin-6, chemokines for CD4+ T cells and/or neutrophils (macrophage inflammatory protein-1α and macrophage inflammatory protein-2), angiogenic factor (vascular endothelial growth factor A), and secondary neutrophil influx, as well as infiltration of CD4+ T cells to exacerbate opacity and angiogenesis in the cornea 14 or/to 28 days post-infection. Our results collectively show that endogenous CXCL10 contributes to recruit the primary neutrophil influx and to affect the expression of cytokines, chemokines, and angiogenic factors, as well as reduce the viral titer and HSK severity.
Enterovirus 71 (EV71) infection has induced fatal encephalitis in thousands of young children in the Asia-Pacific region over the last decade. EV71 infection continues to cause serious problems in areas with outbreaks, because vaccines and antiviral therapies are not available. Lymphocytes are present in brains of infected patients and mice, and they protect mice from infection by decreasing viral burden. The chemokines responsible for recruiting lymphocytes to infected organs are yet to be identified. Among the lymphocyte chemokines detected, high levels of CXCL10 are found in the plasma and cerebral spinal fluid of patients with brainstem encephalitis as compared with the levels of a monokine induced by gamma interferon (Mig). Using a murine model to investigate the induction of CXCL10 by EV71 infection, we observed that EV71 infection significantly enhanced CXCL10 protein expression in the serum and brain with kinetics similar to viral titers in the blood and brain. Brain neurons of infected mice expressed CXCL10. Using wild-type mice and Cxcl10 gene knock-out mice to investigate the role of CXCL10 in EV71 infection, we found that CXCL10 deficiency significantly reduced levels of Mig in serum, and levels of gamma interferon and the number of CD8 T cells in the mouse brain. Absence of CXCL10 significantly increased the mortality of infected mice by 45%, with slow virus clearance in several vital tissues. Our observations are consistent with a model where EV71 infection boosts CXCL10 expression to increase gamma interferon and Mig levels, infiltration of CD8 T cells, virus clearance in tissues and the survival of mice.
論文目次 Abstract in Chinese………………………………………………………………………………………………………Ⅰ
Abstract……………………………………………………………………………………………………………………………………Ⅲ
Acknowledgement…………………………………………………………………………………………………………………Ⅴ
Contents……………………………………………………………………………………………………………………………………Ⅵ
Figure list……………………………………………………………………………………………………………………………Ⅶ
Introduction…………………………………………………………………………………………………………………………1
Materials and Methods…………………………………………………………………………………………………8
Part 1: The role of CXCL10 in HSK…………………………………………………………………8
Part 2: The role of CXCL10 in EV71-induced encephalitis……13
Results……………………………………………………………………………………………………………………………………16
Part 1: The role of CXCL10 in HSK………………………………………………………………16
Part 2: The role of CXCL10 in EV71-induced encephalitis……24
Discussion……………………………………………………………………………………………………………………………30
Conclusion……………………………………………………………………………………………………………………………37
References……………………………………………………………………………………………………………………………38
Figures……………………………………………………………………………………………………………………………………47
Curriculum Vitae……………………………………………………………………………………………………………72
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