臺灣博碩士論文加值系統

病毒生命週期涉及病毒與來自宿主細胞蛋白質、結構和機械的一系列複雜交互作用。抗病毒藥物的發展需要了解這些複雜的病毒感染機制。不幸的是，這幾種關鍵的分子機制在病毒感染過程中知之甚少。單一病毒跟踪是一種即時影像技術，可以成功監測活細胞中個別病毒運輸行為和過程的動力學。超分辨率顯微鏡則能觀察病毒顆粒與細胞次級結構的細節。在我們的研究中，超分辨率顯微鏡有助於我們區分登革病毒進入細胞的多樣途徑。使用單一病毒追踪則證明登革病毒進入細胞後從核內體運輸到自噬小體中。此外我們建立了pH感測器共軛的登革病毒及FRET標記的登革病毒分別用於觀察在自噬體中的酸化和病毒融合。這暗示登革病毒採用自噬作用途徑繞開細胞防禦系統，並進行膜融合釋放病毒基因組以利複制的進行。另一方面，單病毒跟踪方法被用於研究HeLa細胞中牛痘病毒顆粒的運輸途徑。我們的研究結果表明，痘苗病毒運送到初級核內體，其中回收核內體蛋白Rab11和Rab22被徵集參與隨後的病毒運送，然後才能在細胞質中進行病毒脫鞘。

Viral life cycles involve with a series of complicated interactions of the virus with host cells from proteins, structures, and machineries. The development of antiviral drug needs to understand these complicated mechanisms of virus infection. Unfortunately, the several critical molecular mechanisms of virus are poorly understood. Single-virus tracking is a real-time imaging technique that can monitor successfully individual virus trafficking behavior and kinetic processing in live cell. Super-resolution microscopy contributes to visualize the details of virus particles and subcellular structures. In our studies, super-resolution microscopy facilitated us to differentiate the multiport pathways of Dengue virus (DENV) entry. Using single-virus tracking demonstrated that DENV traffics from endosomes to autophagosomes subsequently. In addition, we established that pH sensor conjugating-DENV and FRET labeled-DENV particles were used to visualize acidification and viral fusion in autophagosomes, respectively. It implied DENV takes the autophagic pathway to bypass cellular defense system and proceeds to the membrane fusion to release RNA genome for replication. On the other hand, the single-virus tracking approach was employed to investigate the trafficking routes of Vaccinia virus particles in HeLa cells. Our results showed that vaccinia virus traffics to early endosomes, where recycling endosome markers Rab11 and Rab22 are recruited to participate in subsequent virus trafficking prior to virus core uncoating in the cytoplasm.

Contents
中文摘要 i
Abstract ii
Contents iii
List of Figures iv
List of Tables iv
Chapter 1 Introduction 1
1.1 Virus-host interaction 1
1.2 Visualization of virus 2
1.3 Single-virus tracking 3
1.4 Super-resolution microscopy 5
Chapter 2 A single-virus tracking approach to reveal the interaction of DENV with autophagy during the early stage of infection 8
2.1 Introduction 8
2.2 Materials and methods 11
2.3 Results 17
2.4 Discussion 24
Chapter 3 Revealing autophagy-mediated uncoating process of DENV 42
3.1 Introduction 42
3.2 Materials and methods 47
3.3 Results 55
3.4 Discussion 65
Chapter 4 Intracellular Transport of Vaccinia Virus in HeLa Cells Requires Recycling Endosome Pathway 86
4.1 Introduction 86
4.2 Materials and methods 87
4.3 Results 90
4.4 Discussion 93


List of Figures
Figure 2-1 Induction of autophagy by DENV in Huh7.5 cells 30
Figure 2-2 Purification and characterization of DiD-labeled DENV particles 32
Figure 2-3 Co-localization of DENV particles and autophagosomes 34
Figure 2-4 Single-virus particle tracking by real-time epi-fluorescence microscopy
36
Figure 2-5 Co-transportation of DENV particles and autophagosomes 38
Figure 2-6 The effects of 3-MA and rapamycin on the production of DENV and the distribution of DENV particles 40
Figure 3-1 DENV particles are visualized at single-virus resolution 71
Figure 3-2 DENV particles are transported from endosomes to autophagosomes 73
Figure 3-3 Co-localization of DENV and autophagosomes triggers acidification of
autophagosomes 75
Figure 3-4 FRET pair-labeling DENV (DiI/DiD-DENV) particles are generated and
characterized 78
Figure 3-5 Membrane fusion of DENV particle are visualized in a live cell and in vitro
80
Figure 3-6 DENV membrane fusion occurs in autophagosomes 82
Figure 3-7 85
Figure 4-1 Single-particle tracking reveals vaccinia MV colocalized with early
endosomes 96
Figure 4-2 Vaccinia MV traffics through Rab11-positive recycling endosomes 98
Figure 4-3 Vaccinia MV traffics through Rab22-positive recycling endosomes 100
Figure 4-4 Vaccinia virus does not go through Rab7-positive late endosomes/lysosomes
102


List of Tables
Table 1 Effect of DiD-labeling on the infectivity of DENV 29

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