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系統識別號 U0026-2112201614280300
論文名稱(中文) 登革感染下新穎細胞自噬相關囊泡的形成與傳播
論文名稱(英文) Formation and transmission of novel autophagy-associated vesicle in dengue 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 105
學期 1
出版年 106
研究生(中文) 吳彥緯
研究生(英文) Yan-Wei Wu
學號 S58001399
學位類別 博士
語文別 英文
論文頁數 115頁
口試委員 指導教授-林以行
召集委員-劉校生
口試委員-劉清泉
口試委員-張志鵬
口試委員-林秋烽
口試委員-張堯
口試委員-Robert Anderson
中文關鍵字 登革熱  登革病毒  中和性抗體  輕鏈蛋白3  細胞自噬  登革囊泡  自噬相關蛋 白9  非結構性蛋白1  免疫逃脫 
英文關鍵字 Dengue fever  dengue virus  neutralizing antibody  LC3  autophagy  dengue vesicle  Atg9  NS1  immune evasion 
學科別分類
中文摘要 在全球的感染症中,部分登革疾病以嚴重出血及休克症狀為特徵。登革疾病由登革病毒引起,埃及斑蚊和白線斑蚊能將登革病毒在熱帶與亞熱帶地區傳播。登革病毒可以由細胞釋出的病毒顆粒結合專一受器來進行細胞與細胞間的傳播。中和性抗體能阻止該常規的傳播,然而病人血清中的高濃度中和性抗體卻無法防止登革病毒的感染和疾病,部分肇因於抗體依靠性增強(ADE)。中和性抗體的弱效已經在C 型肝炎病毒和人類免疫缺陷病毒被描述,C 型肝炎病毒能以中和性抗體抗性或是外吐小體來傳播。人類免疫缺陷病毒則能以兩個鄰近細胞間膜的緊密接觸來避免中和性抗體,而在登革病毒則還未發現能避免中和性抗體的途徑。我們利用孔徑3 微米的膜隔開登革病毒感染的供體細胞和綠色螢光蛋白標定的受體細胞來建立轉孔共同培養。登革病毒感染後24 小時,比起緊密接觸共同培養,受體細胞顯示較低的感染率。在緊密接觸共同培養其培養液中加入中和性抗體不會減少受體細胞感染率。鑒於細胞自噬在先前的研究顯示其在登革病毒複製扮演重要角色,我們欲探討其參與在登革病毒緊密接觸共同培養系統中的傳播機制。細胞自噬是一種高度保留的細胞分解胞內受損胞器或是蛋白
質凝聚的途徑。此外,細胞自噬也能以不同於內質網-高基氏體的分泌途徑致使蛋白質分泌。因此我們嘗試連結細胞自噬相關的非傳統分泌途徑與登革病毒避免中和性抗體傳播。首先,我們使用細胞自噬缺陷的供體細胞例如細胞自噬相關蛋白5 (Atg5)低表達Huh7 細胞和Atg5剔除MEF,並觀察到在緊密接觸共同培養系統中登革病毒傳播降低。利用共軛焦顯微鏡的分析,細胞自噬標誌輕鏈蛋白3 (LC3) 和登革病毒套膜蛋白被觀察到從供體細胞中被分泌出來,這些蛋白形成囊泡並黏附到受體細胞上。登革囊泡中含有病毒套膜蛋白、非結構性蛋白1(NS1)、前趨膜蛋白以及油滴,利用NS1 引子進行定量反轉錄聚合脢連鎖反應,確定囊泡中含有登革病毒的核醣核酸,給予核醣核酸脢能減少在登革囊泡的核醣核酸轉染下,受體細胞所表達的非結構性蛋白3(NS3)。這些結果意味著登革囊泡與細胞自噬體相關,且含有感染性的登革病毒核醣核酸。此外,囊泡媒介的傳播不能被外加的抗登革中和性抗體抑制,推測因為病毒核醣核酸被膜所保護,囊泡的膜則直接與目標細胞的膜融合,展開新一輪的感染。重要的是,我們在登革病人血清中也發現這種囊泡,體外分離後依然具有感染力。該細胞自噬相關登革囊泡對於登革病毒在病人體內傳播的角色還需要被研究。由於登革囊泡的尺寸大,膜的來源對囊泡的形成相當重要。細胞自噬相關蛋白9 (Atg9)是細胞自噬相關蛋白家族中唯一具有穿膜構造的蛋白,我們利用共軛焦顯微鏡發現Atg9 在細胞內和登革病毒NS1 有共位現象,這兩者都表達在登革囊泡的表面。共軛焦顯微鏡和免疫沉澱法證實Atg9 和登革病毒NS1 形成一個複合體。在早期病毒複製時,NS1 會表現在內質網上,藉由交互作用。我們證實登革病毒NS1 牽引Atg9 到內質網藉由他們的交互作用,而其突變蛋白則失去交互作用,原因是Atg9 突變造成其細胞內的不正常分布。此外,Atg9 缺陷的供體細胞例如Atg9 低表達Huh7,Atg9 突變高表達Huh7 和Atg9 剔除MEF,導致緊密接觸共同培養系統中受體細胞的感染率下降,原因是Atg9 缺陷的供體細胞產生病毒囊泡的數量下降。這些結果顯現Atg9 在囊泡形成扮演重要的角色。我們的研究發現細胞自噬作用的活化,不僅有利於登革病毒複製,更有助於登革囊泡的形成與傳播。這項研究或許能提供一個可能的免疫脫逃機制,來解釋登革病人中和性抗體為何失效。
英文摘要 Among globally infectious diseases, dengue disease is partly characterized by severe hemorrhage or shock syndrome. Dengue disease is caused by dengue virus (DENV). Aedes egypti or Aedes albopictus can transmit DENV in tropical and subtropical regions. In cell-to-cell
transmission, DENV can spread by cell-free virions binding to specific receptors. Neutralizing antibodies (NAbs) can block such conventional transmission. However, even high titers of NAbs in patients’ sera may not prevent DENV infection and disease partly as a result of antibody-dependent enhancement (ADE). The low efficacy of NAbs in viral infection has already been described for
hepatitis C virus (HCV) and human immunodeficiency virus (HIV). HCV can spread via mechanisms of NAb-resistant or exosome-mediated release. In the case of HIV, the close-contact between membranes of two neighboring cells avoids extracellular NAbs. The mechanism of transmission which can avoid NAbs for DENV has not been defined. We set up a transwell co-culture system using a pore size of 3 m to separate donor infected with DENV and recipient labeled with green fluorescent protein (GFP). After 24 h DENV infection, the recipient cells showed a lower infection rate than recipient cells which were close-contact co-cultured with donor cells. Adding NAbs in the medium of close-contact co-culture system had no effect on infection rate of recipient cells. To clarify the mechanism of DENV transmission in close-contact co-culture system, autophagy was considered because previous studies showed its important role in DENV replication.
Autophagy is a highly conserved cellular pathway to degrade intracellular damaged organelles or protein aggregation. Besides, secretion of several proteins can be triggered by autophagy which is distinguished from endoplasmic reticulum (ER)-Golgi secretory pathway. Therefore, we tried to link autophagy-related unconventional secretion to the DENV transmission avoiding NAbs. First, we used autophagy-deficient donor cells such as Atg5 knockdown Huh7 and Atg5 knockout mouse
embryonic fibroblast (MEF), then observed the reduction of DENV transmission in close-contact co-culture system. By analysis of confocal microscopy, autophagy marker LC3 and DENV envelope (E) proteins were observed to be secreted from donor cells. Those proteins formed
vesicles and attached to recipient cells. Such dengue vesicle contained viral proteins E, nonstructural protein 1 (NS1), prM, and lipid droplet. Using NS1 primer to perform qRT-PCR, the DENV RNA was determined to be contained in vesicle. Treatment with RNAase eliminated the nonstructural protein 3 (NS3) expression in recipient cells transfected by RNA from dengue vesicle. These results imply that dengue vesicle relates to autophagosome and contains infectious DENV RNA. Furthermore, vesicle-mediated transmission could not be blocked by adding anti-dengue NAbs, suggesting that the infectious viral RNA was protected by a membrane. Such membrane directly fused to the plasma membrane of target cells to initiate a new round of viral infection.
Importantly, we also detected dengue vesicles in a patient’s serum and showed that they were infectious ex vivo. The role of dengue vesicle for DENV spread in patient still need to be clarified. Due to the big size of dengue vesicle, membrane source is important for vesicle formation. Among Atg proteins family, Atg9 is the only one containing transmembrane domains for membrane
trafficking. We found that Atg9 colocalized with NS1 in the cytosol and both of them were on the surface of dengue vesicle. Confocal microscopy and co-immunoprecipitation confirmed that Atg9 and NS1 were in an interaction complex. During early viral replication, NS1 is expressed on the ER. We confirmed that NS1 interacted with Atg9 to recruit it to ER via their interaction, and Atg9 mutant lost the interaction. It was caused by an abnormal distribution of Atg9 mutant in the cell. Besides, Atg9 deficient donor cells, such as Atg9 knockdown Huh7, Atg9 mutant-overexpressing Huh7 and Atg9 knockout MEF, had a decreased infection rate of recipient cells in the close-contact co-culture system. This was caused by the reduced numbers of vesicles in Atg9 deficient donor cells. These results show that Atg9 plays an important role in the formation of dengue vesicle. Our study clarifies that the induction of autophagy is not only related to DENV replication but also contributes
to the formation and transmission of dengue vesicle. This discovery may explain the inefficiency of antibody neutralization upon DENV infection as a potential immune evasion mechanism in dengue patients.
論文目次 中文摘要 1
Abstract 3
誌謝 6
Contents 8
Figure l ist 11
Abbreviation index 14
I. Background 15
Dengue disease 15
Dengue virus (DENV) 15
The entry of DENV 16
Host responses against DENV 17
Antibody escape in dengue disease 18
Autophagy 19
Atg9 vesicles 21
Autophagosome formation site 21
DENV and autophagy 22
Autophagy-related unconventional secretion 23
II. Specific aims 25
Schematic illustration of specific aims 26
III. Materials and methods 27
A. Materials 27
a. Cell line 27
b. DENV 27
c. Antibody 27
d. si/shRNA plasmid and primer 30
e. Reagent 31
f. Experimental consumable 35
g. Instrument 35
B. Methods 37
Cell culture 37
DENV culture and plaque assay 37
Isolation of dengue virions and vesicles 38
Monoclonal antibody preparation and purification 38
Immunofluorescence staining assay and surface staining 38
Co-immunoprecipitation 39
Western blotting 39
Direct and transwell culture system 39
Transmission electron microscopy (TEM) and immunogold stain 40
RT-PCR and qRT-PCR 40
Statistical analysis 40
IV. Results 41
Close-contact co-culture system enhances DENV infection rate. 41
Autophagy-deficient donor cells decrease transmission rate in closecontact co-culture system. 42
Extracellular vesicles contain DENV proteins and autophagy marker LC3. 43
Reduction of dengue vesicles in the DENV-infected autophagy deficient cells. 44
Infectious autophagy-associated dengue vesicles can escape antibody neutralization. 44
Viral and host proteins locate on the vesicle.45
Intracellular interaction between NS1 and Atg9. 46
Interaction of Atg9 and NS1 at ER. 47
Atg9 deficiency decreases the numbers of viral vesicles. 47
Atg9 deficiency decreases the infection rate in close-contact co-culture system. 47
V. Discussion 49
Roles of autophagy in DENV replication 49
Effect of bafilomycin A1 in dengue vesicle 50
Interaction between NS1 and Atg9 51
Secretion of dengue vesicle 52
Entry and elongation of dengue vesicle 54
Regulation of vesicle trafficking 55
Inhibitory strategy for dengue vesicle 55
VI. Conclusion 57
Schematic illustration of conclusion 58
VII. References 59
VIII. Figures 72
Curriculum Vitae 111
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