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系統識別號 U0026-2011201719102900
論文名稱(中文) 登革病毒非結構性蛋白一引起血管滲漏之機制
論文名稱(英文) Study on the mechanisms of dengue virus nonstructural protein 1-induced vascular leakage
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 106
學期 1
出版年 106
研究生(中文) 陳泓如
研究生(英文) Hong-Ru Chen
電子信箱 s58011182@mail.ncku.edu.tw
學號 S58011182
學位類別 博士
語文別 英文
論文頁數 130頁
口試委員 指導教授-葉才明
召集委員-林以行
口試委員-劉清泉
口試委員-劉校生
口試委員-伍安怡
口試委員-Robert Anderson
中文關鍵字 登革病毒(DENV)  血管滲漏  非結構蛋白1(NS1)  巨噬細胞遷移抑制因子(MIF)  自噬體  糖萼  肝素酶(HPA-1)  金屬蛋白酶-9(MMP-9) 
英文關鍵字 dengue virus (DENV)  vascular leakage  non-structural protein 1 (NS1)  macrophage migration inhibitory factor (MIF)  autophagy  glycocalyx  heparanase (HPA-1)  metalloproteinase-9 (MMP-9) 
學科別分類
中文摘要 登革病毒(DENV)是最常見的由蚊子傳播之黃病毒,感染後會引起輕度登革熱,或較嚴重的登革出血熱(DHF)和登革休克症候群(DSS)。 DHF / DSS的主要特徵之一是血管滲漏。然而,DENV感染導致血管通透性增加的機制目前尚不清楚。 DENV非結構蛋白1(NS1)是在黃病毒間高度保留的蛋白,其血液中的濃度與疾病的嚴重程度呈正相關。此外,NS1在血液循環中的積累也與DENV感染患者處於危急階段的時間一致。因此,我們假設NS1為DENV引起血管滲漏的主要因子。
我們證明NS1重組蛋白能誘導血管滲漏,並且還增加促炎細胞因子巨噬細胞移動抑制因子(MIF)的分泌。而後我們調查MIF是否能夠誘導血管滲漏。結果顯示,MIF除了可誘導內皮細胞中的自噬形成,若抑制細胞自噬則可減弱MIF所所誘導之細胞連結的破壞和血管滲漏,表明MIF藉由引起自噬機制而造成血管滲漏。因此,我們進一步提出,NS1通過MIF誘導的自噬引起血管滲漏。結果顯示,抑制MIF可以減少DENV NS1誘導的自噬形成,而抑制自噬形成亦能減緩NS1誘導的血管滲漏。
通過應用以Schwarzman反應為基礎的小鼠模型,我們進一步證實了DENV NS1可誘導出血。出血組織的免疫組織化學染色顯示NS1,但非其他結構蛋白,可誘導內皮糖萼的降解。細胞實驗表明NS1可以誘導內皮細胞分泌肝素酶(HPA-1),而抑制HPA-1可減少NS1誘導的內皮糖萼降解。另外我們亦發現DENV NS1可以誘導白血球而非血管內皮細胞分泌MMP-9,而所得之上清液可增加血管內皮之通透性。有趣的是,抑制MIF可抑制NS1誘導的蛋白酶HPA-1和MMP-9分泌。來自DHF患者的血漿樣品也顯示MIF和內皮糖萼降解的指標(CD138)濃度呈正相關,表明MIF在登革病毒誘導內皮糖萼降解中具有重要作用。
最後,我們證明抑制MIF在細胞和小鼠實驗中可抑制DENV NS1誘導的血管滲漏。本研究顯示,DENV NS1通過破壞血管內皮細胞間的連接和引發內皮糖萼的降解造成血管滲漏,而MIF是兩種途徑的中樞調節因子。本研究將提供治療和預防DHF / DSS中血管滲漏的治療靶點。
英文摘要 Dengue virus (DENV) is the most common mosquito-borne Flavivirus, it causes mild dengue fever or severe diseases including dengue hemorrhagic fever (DHF) and shock syndrome (DSS). One of the characteristic features of DHF/DSS is vascular leakage. However, the mechanisms of how DENV infection causes the increase in vascular permeability remain unclear. DENV non-structural protein 1 (NS1) is a highly conserved protein among flaviviruses, and its level is positively-correlated with the severity of the disease. Furthermore, the accumulation of NS1 in the circulation is also consistent with the critical phase of DENV-infected patients. Based on these oberservations, we hypothesized that NS1 is responsible for DENV-induced vascular leakage.
We demonstrated that recombinant NS1 induced vascular leakage, and it also increased the secretion of pro-inflammatory cytokine macrophage migration inhibitory factor, MIF. We then investigated whether MIF is able to induce vascular leakage. The results showed that MIF induced autophagy formation in endothelial cells, and that inhibiting autophagy attenuated MIF-induced disruption of cell-cell junction and vascular leakage. These results indicate that MIF induces vascular leakage through an autophagy-dependent mechanism. We then investigated whether NS1 causes vascular leakage through MIF-induced autophagy. The results showed that inhibiting MIF attenuated DENV NS1-induced autophagy formation, and either inhibiting MIF or autophagy rescued NS1-induced vascular leakage.
By applying a mouse model based on Schwarzman reaction, we further demonstrated that DENV NS1 induced hemorrhage. Immunohistochemistry staining of hemorrhagic tissues showed that NS1, but not structural proteins, induced the degradation of endothelial glycocalyx. In vitro experiments further demonstrated that NS1 induced endothelial cells to secrete heparanase (HPA-1), and inhibiting HPA-1 attenuated NS1-induced endothelial glycocalyx degradation. In addition, DENV NS1 induced white blood cells but not endothelial cells to secrete MMP-9, and the resultant supernatant increased endothelial permeability. Interestingly, the proteinases HPA-1 and MMP-9 secretion was diminished by inhibiting MIF. There was a positive correlation between the concentration of MIF and CD138 in the plasma of DHF patients, indicating that MIF plays an important role in inducing endothelial glycocalyx degradation.
In the end, we demonstrated that inhibiting MIF rescued DENV NS1-induced vascular leakage, both in vitro and in vivo. This study revealed that DENV NS1 induces vascular leakage through disruption of endothelial cell-cell junction and degradation of endothelial glycocalyx, and MIF is the central modulator in both pathways. These results provide potential therapeutic targets for treating and preventing vascular leakage in DHF/DSS.
論文目次 Abstract in Chinese ………………………………………………..………..I
Abstract………...…………………………………………………………III
Acknowledgements………………………………………………………….V
Contents………………………………………………………………....…VII
List of figures........................................................…………….……………XI
List of figures in appendixes......................................................................XIII
Abbreviation index……………………………...……………………......XIV
I. Background…………………………………………………………....1
A. Dengue fever………………………………………………………….....1
A.1 General information of dengue fever……………………………......1
A.2 Dengue virus…………………………………...…………………....2
A.2.1 The structure of dengue virus……………………………..…....2
A.2.2 Dengue virus nonstructural protein 1 (NS1)………………....…2
A.2.2.1 The structure, expression and secretion of NS1…..….....2
A.2.2.2 NS1 and vascular leakage……………………………...3
B. Blood vessels…………………………………………………………....4
B.1 The structure of blood vessels………………………………….......4
B.2 Endothelial barrier……………………………………………….....5
B.2.1 Regulation of endothelial barrier……………………………......5
B.2.2 Endothelial barrier: paracellular pathway…………………….....5
B.2.3 Endothelial barrier: glycocalyx………………………………....6
C. Vascular leakage………………………………………………………...7
C.1 Vascular leakage in diseases………………………………...……..7
C.2 Methods for measuring vascular leakage………………………......8
D. Cytokines and vascular leakage in DENV infection…………………..10
D.1 Cytokine storm…………………………………………………..10
D.2 Macrophage migration inhibitory factor (MIF)………………….10
D.2.1 MIF signaling and diseases…………………………………10
D.2.2 The role of MIF in dengue fever……………………………11
E. Autophagy………………………………………………………………12
E.1 Autophagy pathway……………………………………………...12
E.2 Autophagy in diseases……………………………………………14
E.3 MIF and autophagy………………………………………………15
II. Specific aims…………………………………………………………17
III. Materials and methods……………………………………………...19
A. Materials…………………………………………………………..19
B. Methods…………………………………………………………...26
IV. Results………………………………………………………………..36
DENV NS1 disrupts endothelial barrier function…………………………………36
DENV NS1 induces MIF secretion………………………………………………..37
MIF disrupts endothelial barrier function through deconstruction of cell-cell
junctions……………………………………………………………………..37
MIF induces autophagy in endothelial cells……………………………………….38
Autophagy mediates MIF-induced dysfunction of the endothelial barrier………..39
ERK signaling mediates MIF-induced autophagy and vascular leakage………….41
DENV NS1 induces autophagy formation through MIF…………………………..42
MIF and autophagy mediate DENV NS1-induced vascular leakage through the
disruption of cell-cell junction………………………………...…………….43
Inhibiting MIF attenuates DENV NS1-induced endothelial hyperpermeability…..44
DENV NS1 induces glycocalyx degradation ……………………………………..45
HPA-1 mediates NS1- induced glycocalyx degradation…………………………..46
MIF is involved in DENV-NS1-induced glycocalyx degradation………………...47
MMP-9 is involved in NS1-induced glycocalyx degradation……………………..48
MIF mediates the effect of MMP-9 in DENV NS1-induced glycocalyx
degradation…………………………...……………………………………...49
The secretion profiles of MIF, HPA-1, MMP-9 in vivo and in clinical samples….50
Inhibiting MIF attenuates DENV NS1-induced endothelial glycocalyx
degradation…...……………………………………………………………...51
V. Discussion…………………………………………………………….52
NS1: friends or foes for flavivirus?..........................................................................52
DENV NS1 and anti-NS1 antibodies in DENV-induced pathogenesis…………....52
The involvement of MIF in DENV infection……………………………………...54
Early stage of MIF-mediated vascular leakage: reorganization of actin
cytoskeleton ...................................................................................................55
Late stage of MIF-mediated vascular leakage: autophagic degradation .................56
MIF-induced signaling pathways in inducing autophagy and vascular leakage…..57
The correlation of autophagy and vascular leakage……………………………….58
The importance of autophagy pathway in DENV infection……………………….58
Two important proteinases mediating DNEV NS1-induced glycocalyx degradation:
MMP-9 and HPA-1……………………...........……………………....……..59
The central modulator of DENV NS1-induced vascular leakage: MIF……….......60
Clinical implications ...............................................................................................62
VI. Conclusion............................................................................................64


VII.
References..........................................................................................
..65
Table...............................................................................................
......81
Table 1. The demographic information and clinical laboratory data of the study
population....................................................................81
VIII.
Figures.............................................................................................
.....82
IX.
Appendixes........................................................................................120
X. Curriculum
Vitae..............................................................................128
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