日本腦炎病毒(Japanese encephalitis virus，簡稱JEV)，屬於蚊子傳播的黃質病毒(Flavivirus)，為引起病毒性腦炎之主要病因。所有蚊媒黃質病毒在感染細胞後會產生一段非編碼次基因體RNA (subgenomic RNA，簡稱sfRNA)，其序列為病毒基因體3’-端未轉譯區(untranslated region，簡稱UTR)中高度保守的序列。在其它黃質病毒的研究顯示sfRNA是經由細胞中的核酸外切酶XRN1 (5’-to-3’ exoribonuclease XRN1)降解病毒基因體後的產物，並在對抗宿主抗病毒反應中扮演重要的角色。然而JEV感染產生sfRNA的機制及其如何幫助病毒躲避宿主的抗病毒機制尚不清楚。雖然利用活體外降解病毒基因體3’-末端800個核苷酸可以產生 sfRNA，但在活體內將細胞中XRN1基因剔除(knockout)不影響sfRNA的生成。利用定點突變證明，病毒複製酶(RNA-dependent RNA polymerase，簡稱RdRp)的活性及3’-UTR中stemloop II (SLII)的結構決定sfRNA的生合成。利用活體外病毒複製酶反應實驗(in vitro RdRp assay)證明，RdRp蛋白質會結合在負股 nt 10431-10566 RNA模板可能為sfRNA啟動子的位置，並可做出RNA產物。綜合以上結果顯示JEV sfRNA可能是先經由轉錄作用生成，再由XRN1或其它核酸外切酶修飾而成。此外，利用轉染方式過量表現sfRNA於JEV感染的細胞會減少細胞病癥(cytopathic effect，簡稱 CPE)、降低細胞週期中sub-G1期之DNA含量、減少病毒感染引起細胞內粒腺體膜電位下降的產生、促使抗細胞凋亡之蛋白激酶Akt磷酸化、抑制多ADP核糖聚合酶(PARP)的切割等多種細胞凋亡因子的指標。此外，過量表現sfRNA時，病毒蛋白質NS5的表現量及病毒力價皆有顯著下降，且干擾素調控因子-3磷酸化的表現量與sfRNA含量成反比。這些結果顯示，sfRNA會降低JEV感染誘發之細胞凋亡訊息路徑，以及具有調控病毒複製能力，進而延緩JEV感染造成的細胞死亡。本研究是首次證明日本腦炎病毒sfRNA生成並非由XRN1降解病毒基因體而來，且sfRNA具有自我調控之能力，其在病毒及宿主間可能扮演重要之調節角色。

Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus and is a major cause of viral encephalitis. All mosquito-borne flaviviruses accumulate an abundant noncoding subgenomic RNA (sfRNA) representing the highly conserved region of the 3’ untranslated region (UTR) in infected cells. It has been reported that sfRNA of other flaviviruses resulted from stalling of host 5’-to-3’ exoribonuclease XRN1 at the highly structured RNA of the 3’ UTR and it plays a role against host antiviral responses. However, the formation mechanism and biological function of JEV sfRNA remains largely unclear. Although XRN1 digestion of a 3’-terminal 800-nt RNA could stall at a position to generate the sfRNA in vitro, we found that knocking out XRN1 had no effect on the accumulation of sfRNA in JEV-infected cells. Mutagenesis studies revealed that the stemloop II (SLII) at the 3’ UTR and functional RNA-dependent RNA polymerase (RdRp) are required for the formation of sfRNA. Templates representing the putative promoter region exhibit promoter activity suggesting that the JEV sfRNA could be transcribed initially and then be trimmed by XRN1. Furthermore, transfecting excess amounts of sfRNA into JEV-infected cells reduced the virus-induced cytopathic effect, decreased the sub-G1/DNA content, rescued the mitochondrial membrane potential changes, increased the level of phosphorylated Akt, blocked the cleavage of poly ADP ribose polymerase (PARP), and downregulated viral translation and virus titers. Taken together, these results indicate that the sfRNA has the ability to rescue virus-induced apoptosis. The extent of interferon regulatory factor-3 (IRF-3) phosphorylation is inversely correlated with the presence of the sfRNA by comparison recombinant viruses with or without the sfRNA. This is the first report demonstrated that JEV sfRNA is dispensable by XRN1 degradation. Accumulation of the sfRNA plays a role to modulate apoptosis of infected cells and prolongs cell survival.

PART I
The conserved stem-loop II structure at the 3’ untranslated region of Japanese encephalitis virus genome is required for the formation of subgenomic flaviviral RNA 1
I.1 INTRODUCTION 3
I.2 MATERIALS AND METHODS 7
1. Cells and virus 7
2. Plasmids and site-directed mutagenesis 7
3. XRN1 RNA interference, Western, and Northern analyses 9
4. Nuclease assays 10
5. Transfection 11
6. Plaque assay 11
7. Electrophoretic mobility shift assay (EMSA) 12
8. In vitro RdRp assay 13
I.3 RESULTS 15
1. Abundant amounts of the JEV sfRNA accumulated in XRN1-depletion cells 15
2. The stem-loop II (SLII) structure is required for the formation of the sfRNA 17
3. Viral replication is essential for abundant accumulation of the JEV sfRNA 20
4. Viral RdRp binds to the putative promoter and synthesizes RNA products 20
I.4 DISCUSSION 23

PART II
Accumulation of the sfRNA in Japanese encephalitis virus-infected cells inhibits apoptosis and prolongs cell survival 31
II.1 INTRODUCTION 33
II.2 MATERIALS AND METHODS 39
1. Cells and viruses 39
2. RNA transfection 39
3. Flow cytometry assay 40
4. Detection of apoptotic cells 40
5. Anti-Fas antibody induced apoptosis 41
6. Western blot analysis 41
II.3 RESULTS 43
1. Transfection of sfRNA reduces JEV-induced apoptosis 43
2. sfRNA stabilizes the mitochondrial membrane potential in JEV-infected cells 44
3. sfRNA reduces the PARP cleavage and upregulates Akt phosphorylation in JEV-infected cells 44
4. Transfecting of sfRNA promotes phosphorylation of Akt but does not protect cells from Fas-dependent apoptosis 46
5. Transfection of sfRNA downregulates viral translation and virus titers 47
6. sfRNA is involved in regulation of antiviral responses 48
II.4 DISCUSSION 51
REFERENCES 59
TABLES AND FIGURES 67

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