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研究生：	蔡佩汝 Tsai, Peiju
論文名稱：	C 型肝炎病毒從急性至慢性感染造成宿主生物恆定的變化之研究 Study on the alterations of host homeostasis induced by hepatitis C virus from acute to chronic infections
指導教授：	楊孔嘉 Young, Kung-Chia
學位類別：	博士 Doctor
系所名稱：	醫學院 - 基礎醫學研究所 Institute of Basic Medical Sciences
論文出版年：	2019
畢業學年度：	107
語文別：	英文
論文頁數：	109
中文關鍵詞：	C 型肝炎病毒、慢性感染、報導蛋白 SEAP 、比較蛋白質體質譜分析法
外文關鍵詞：	Hepatitis C virus, Chronic infection, SEAP reporter system, Comparative proteomics
相關次數：	點閱：75 下載：2
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C 型肝炎病毒在臨床易造成慢性感染。然而，目前病毒如何在急性期轉慢性期間改變細胞生理仍然未知。因此假設 C 型肝炎病毒與宿主交互作用，能改變感染急性期轉慢性期間的細胞生理，導致肝細胞病變，造成脂肪肝、肝硬化至肝癌。為此首先建立細胞感染報導系統，可將細胞長期感染的特徵定義為急性期 (上升期，上升穩定期，下降期，寂靜期)與慢性期。接著探討脂肪與病毒蛋白在長期細胞感染系統與病毒核心蛋白轉殖小鼠的脂肪小滴與脂肪累積量的變化。其次，利用比較蛋白質體質譜分析法和人類蛋白質資料庫鑑定急性與慢性期共五時期之病毒感染細胞。五時期之病毒感染細胞各自具有特殊蛋白質群，進一步將這些蛋白質用蛋白質功能分選平台軟體進行蛋白質功能分選。結果顯示，大部分宿主蛋白五期之表現趨勢可歸類為上升期至上升穩定期表現下降，上升穩定期至慢性期表現上升，為第一型趨勢。此時宿主的生理特徵，如：外吐小體、鈣黏蛋白結合功能、黑素體和核糖核酸結合功能會與病毒慢性感染有關。將外吐小體相關蛋白再次功能分選，發現膜吐作用蛋白可集合成同一種表現趨勢，為第二型趨勢。此外，預測AIFM1、API5和SMC4決定了急性感染期細胞的早期細胞凋亡、細胞復活和細胞停滯。結論來說，本研究成功定義感染細胞長期感染的特徵與臨床相似。本研究能提供大量預測病毒長期感染下之生理機制，藉由改變這些細胞生理特徵會支持感染細胞長期存活於細胞中。

Hepatitis C virus (HCV) is prone to establish chronic infection in a natural course of infection. However, the alterations of host homeostasis from HCV acute to chronic infection are not well understood. We hypothesize that HCV might interact with the host biological processes for a change of microenvironment from viral acute to chronic infections, and further develop liver diseases. In this study, we first established a platform of HCV infected reporter system to define the different stages of HCV infection as acute (exponential, plateau, declined, silencing phases) and chronic stages. Additionally, the correlations of lipids and viral proteins were examined during HCV infections by the characters of lipid droplets and the accumulated levels of lipid contents. Further, the iTRAQ labeling couple with LC-MS/MS analysis and SwissProt Protein Database were exxploited to clarify the differences of protein expressions between the HCV four acute phases and chronic stage. The identified proteins were clustered as predicted biological pathways through two major databases: GeneGo and KEGG by the ClueGO plus CluePedia software on the platform of Cytoskype. Overall host proteins in HCV-infected cells exhibited kinetic pattern 1, in which cellular expression was downregulated from the acute exponential to plateau phases, reached a nadir, and was then elevated at the chronic stage. The predicted functional pathways were the categories involving extracellular exosome, cadherin binding, melanosome, and RNA binding. The host proteins in the category of extracellular exosome could by classified into terms of endocytosis, endocytic system, ER-Golgi transport, and exocytosis, and the proteins involved in the membrane-budding pathway exhibited kinetic pattern 2, in which their expression was distinctly downregulated at the chronic stage. Moreover, AIFM1, API5, and SMC4 were differentially regulated proteins which might participate in early apoptosis, anatasis and cell cycle arrest. In conclusion, the potential biological pathways from the long-term HCV infection system might provide a new sight of HCV chornic infection for future investigation.

I. Introduction----------- 1
1. The HCV genome and viral proteins-------- 1
2. Epidemioloy, pathology, and current therapies of HCV---- 1
3. HCV life cycle---------- 2
 3-1. Viral entry----------- 2
 3-2. Viral replication---------- 2
 3-3. Viral assembly and release-------- 3
4. The definition of HCV acute and chronic infection----- 3
5. HCV cell-based exogenous foreign reporter systems----- 4
6. Comparative proteomics analysis-------- 5
7. HCV and intracellular transport-------- 5
8. Apoptosis and cell cycle arrest during HCV infection------ 6
 8-1. The definition of early and late apoptosis------- 6
 8-2 Reversible apoptosis (anatasis) ------- 6

II. Rationale of this study--------- 8

III. Specific aims---------- 9

IV. Materials and methods-------- 10
  1. Cells and antibodies---------- 10
  2. HCVcc preparation and viral titer determination----- 10
  3. Secreted alkaline phosphatase assay------- 10
  4. Trypan Blue exclusion test of cell viability------ 10
  5. Extracellular viral infectivity determination------ 11
  6. HCV RNA quantification-------- 11
7. Immunoblot assay---------- 11
8. Immunofluorescence stain-------- 12
9 Triglyceride and cholesterol quantification assay----- 12
10. iTRAQ protein sample preparation------- 12
11. iTRAQ labeling, basic reversed-phase chromatography and LC-MS/MS analysis- 12
12. Protein identification and quantitation------ 13
13. The software of functional pathways prediction----- 13
14. Apoptosis analysis---------- 14
15. Cell cycle analysis---------- 14
16. Statistical analysis---------- 14

V. Results----------- 15
  1. Establishment of HCV chronic infection reporter system----- 15
 1-1. HCV infection time was divided into acute and chronic stages--- 15
     1-1-1. HCV activity could be long-term monitored though reporter system in vitro.
     1-1-2. The dynamic activities of parameters during HCV infection were similar to the extracellular SEAP reporter curve.
 1-2. The HCV induced hepatocyte steatosis pathology could be monitored in reporter cells and in HCV transgenic mice------ 16
 1-2-1. Lipid droplets changed in HCV chronic infected cells
 1-2-2. The levels of intracellular lipids changed in HCV chronic infected cells
 1-2-3. The weights of HCV core transgenic and wild type mice
 1-2-4. Lipid profiles changed in mice serum and liver during aging
   1-3. Cell growth was changed before viral activity became silencing --- 18
   1-4. HCV primary infection inhibit viral superinfection---- 18
     1-4-1. HCV inhibit the viral secondary infection 
     1-4-2. HCV chronic infection attenuated the receptor expression

  2. Biological processes of HCV acute to chronic infection were predicted by proteomics------------- 20
   2-1. iTRAQ coupling with LC-MS/MS analysis, protein clustering, and ClueGo-   CluePedia prediction--------- 20
   2-2. HCV controlled the intracellular trafficking----- 21
     2-2-1. Endocytosis
     2-2-2. Endocytic system
      2-2-2-1. From plasma membrane to MVB
      2-2-2-2. From MVB to plasma membrane
      2-2-2-3. Endosomal recycle
     2-2-3. Secretory system
      2-2-3-1. Classical secretory pathway
      2-2-3-2. Unconventional pathway
      2-2-3-3. Extracellular space

  3. The candidate pathways and their proteins associated with the HCV infection-- 32
   3-1. Apoptosis was reversed at HCV actue stage----- 32
3-1-1. HCV infection induced early apoptosis in HCV acute stage
3-1-2. The early apoptosis rate of infected cells could correlate with apoptosis signal 
which was predicted in HCV acute stage. 
3-1-3. API5 supported HCV infected cells turned to survive by after enhancing 
apoptosis signal pathway
3-1-4. AIFM1 was the apoptotic factor which induced early apoptosis
3-2. HCV induced cell cycle arrest-------- 34
3-2-1. HCV altered cell cycle in HCV acute stage.
3-2-2. SMC4 controlled the HCV infected cells arrested in G2/M phase at acute stage.
3-2-3. HCV controlled the subunits of proteasome during HCV chronic infection.

VI. Discussion---------- 36
1. The switching of secretion process determined HCV infected cells entered to the silencing 
phase and chronic stage.---------- 36
2. HCV genotypes determined the size of lipid droplets. ----- 37
3. Cholesterol level determined the HCV activity. ------- 38
4. Cholesterol might flux to lysosome during HCV declined phase. ---- 38
5. Profiling of the differential hepatic protein kinetics yielded the association of intracellular 
transport function with long-term cultured HCV-infected hepatocytes. --- 39
6. HCV controlled the COPII vesicle which correlated with the secretion road of ALB.-- 41
7. Endosomal system was essential for HCV secretion. ----- 42
8. HCV infection induced the phophatidleserine exposure on the outer plasma membrane-43
9. HCV infection controlled the cell survive. ------- 44

VII. Conclusion---------- 46

VIII. References----------- 48

IX. Tables----------- 60
Table 1. The samples of indicated time points in compared groups label with four iTRAQ tags and the number of total gained protein in each compared groups--- 60
Table 2. The total protein numbers of upregulated, downregulated, no changed and opposite expression in five days/stages. ----- 61
Table 3. The predicted biological pathways were regulated during whole HCV chronic infection period. --------- 62
Table 4. The proteins in membrane budding and melanosome were associated with HCV 
infection----------- 64
Table 5. The apoptosis pathway was predicted from the upregulated or downregulated proteins of five stages. -------- 65
Table 6. The cell cycle process was predicted from the upregulated or downregulated proteins of five stages. -------- 66

X. Figures----------- 67
Figure 1. The curve of extracellular SEAP activity of acute to chronic infected cells. - 67
Figure 2. The change of extracellular viral infectivity of acute to chronic infected cells. -- 68
Figure 3. The alteration of viral RNA levels of acute to chornic infected cells. --- 69
Figure 4. The alteration of viral proteins of acute to chornic infected cells. --- 70
Figure 5. The alteration of lipid droplets of mock and of acute to chornic infected cells. -- 71
Figure 6. The intracellular lipids of mock and of HCV acute to chornic infected cells. -- 73
Figure 7. Mice body weights of wild type and HCV coreTg mice----- 74
Figure 8. The lipid profiles of 7 to 12-week old male mice ---- 75
Figure 9. The cell number of mock and infected cells. ------ 76
Figure 10. HCV infection inhibited the same virus secondary infection. --- 77
Figure 11. CD81 expression changed during HCV chronic infection. ---- 78
Figure 12. The viral protein expressions and extracellular viral infectivity of five stages. - 79
Figure 13. The expression trend of prediction pathway networks in the five stages. - 80
Figure 14. 227 intracellular transport proteins in category of “extracellular exosome”. -- 81
Figure 15. The 77 trafficking proteins those involved in vesicle transport. -- 82
Figure 16. The 36 proteins expressing pattern 1 involved in vesicle transport. -- 84
Figure 17. The 41 proteins expressing non-pattern 1 involved in vesicle transport. -- 86
Figure 18. The 15 proteins expressing pattern 2 involved in vesicle transport. -- 88
Figure 19. The 26 proteins expressing with non-pattern 1/2 involved in vesicle transport.- 89
Figure 20. The proteins in term of endocytosis. ------ 90
Figure 21. The proteins in term of endosome to MVB. ----- 91
Figure 22. The proteins in term of MVB to plasma membrane. ----- 92
Figure 23. Confirm the expression of apolipoprotein E. ------ 93
Figure 24. The proteins in term of endosomal recycle system. ---- 94
Figure 25. The proteins in term of intracellular transport from ER to trans-Golgi. - 95
Figure 26. The secretory proteins in cells during HCV chronic infection. --- 97
Figure 27. The apoptosis assay of HCV acute infected stage. ---- 98
Figure 28. The iTRAQ ratios of apoptotic proteins during HCV chronic infection. -- 99
Figure 29. The cell cycle assay of HCV acute infected stage. ---- 100
Figure 30. The iTRAQ ratios of cell cycle proteins during HCV chronic infection. - 102
Figure 31. proteasomal proteins of cell cycle process. ------ 103

XI. Appendix----------- 104
1. The flowchart of proteomics analysis------- 104
2. The genes and their names of proteins------- 106

XII. Author----------- 109
                                    

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