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研究生:葉曉芬
研究生(外文):Siao-FenYeh
論文名稱:在細胞和動物模式下金銀花茶及其誘發表現的微小RNA let-7a對登革二型病毒的抑制效果
論文名稱(外文):Inhibition of dengue virus type 2 infection by honeysuckle and its induced microRNA let-7a - an in vivo and in vitro study
指導教授:劉校生
指導教授(外文):Hsiao-Sheng Liu
學位類別:碩士
校院名稱:國立成功大學
系所名稱:微生物及免疫學研究所
學門:生命科學學門
學類:微生物學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:71
中文關鍵詞:登革病毒金銀花微小RNA let-7a抗病毒
外文關鍵詞:Dengue virusHoneysucklelet-7aanti-virus
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登革病毒為黃熱病毒科並帶有套膜的正股RNA的病毒。登革病毒可導致輕微的登革熱,嚴重的登革出血熱和登革休克症候群。世界衛生組織統計登革病毒每年在全球造成嚴重感染。受限於不同血清型與抗體依賴型增加的現象,目前仍無有效的疫苗或臨床抗病毒之藥物。因此,開發能預防或治療的天然物為努力目標之一。已知金銀花茶餵食給9周大C57BL/6公鼠,血液中微小RNA有高度表現之現象。金銀花是否可藉由刺激宿主體內微小RNA表現而抑制登革病毒呢﹖微小RNA為長度約22個核苷酸長,許多微小RNA可調控病毒感染已被報導。因此,微小RNA是否可抑制登革病毒之感染值得探討。金銀花是一種傳統中藥,被用來廣泛治療風熱、發炎和病毒感染症等疾病,並可抑制單純疱疹病毒(HSV)、人類免疫缺失病毒(HIV)、呼吸道細胞融合病毒(RSV)、A型流感病毒和嚴重急性呼吸道症候群(SARS)。微小RNA let-7a為小鼠受到金銀花刺激而高度表達的微小RNA之一,經Vita軟體預測可以辨認登革二型病毒之NS1基因﹙3313-3333﹚。6天大ICR仔鼠血液中發現let-7a受到金銀花的刺激亦有表現上升之情形,顯示金銀花有可能經由let-7a來抑制登革病毒複製。本研究首先以帶有登革二型病毒NS1目標基因序列的冷光報導質體,證實let-7a確實能藉由辨認其目標基因序列而抑制其冷光酵素活性。在肝癌細胞Huh7中,let-7a可抑制登革二型病毒NS1 RNA (40%)與NS1蛋白質表現 (20%),進一步發現let-7a可抑制登革病毒負股RNA之表現,顯示let-7a能影響登革病毒的複製。登革病毒感染小鼠之模式中,感染前後餵食金銀花茶再以顱內注射方式感染6天大仔鼠﹙PL046, 2.5 x 105 PFU﹚,發現金銀花能延後1天病徵產生並降低疾病嚴重程度,鼠腦內登革病毒NS1RNA(20%)及蛋白質(70%)及病毒量(45%)皆降低;在治療模式下,先以顱內注射感染病毒,再餵食金銀花茶,金銀花能延長病鼠存活時間2天、延後病徵產生2天並降低疾病嚴重程度,此外,鼠腦登革病毒之病毒NS1RNA(78%)以及蛋白質(52%)與病毒量(44%)皆有下降之趨勢,顯示金銀花確實能影響受感染之小鼠內登革二型病毒之複製與致病性。此外小鼠感染登革病毒後,以顱內注射方式注入let-7a 2次,結果顯示let-7a亦能延後病徵之發生,並對鼠腦內登革病毒之NS1 RNA(26%)與NS1蛋白質(50%)表現有抑制現象,對於病毒量抑制達到90%以上。以上結果顯示金銀花抗登革病毒的能力可能與刺激let-7a表現有關。總言之,本研究首度發現金銀花具有抗登革二型病毒感染之能力,也能藉由誘發let-7a表現及降解登革NS1基因或阻斷蛋白之合成來影響登革二型病毒的感染。同時也發現let-7a可以藉由直接辨認登革病毒NS1基因的轉譯區序列來抑制病毒複製。這發現可運用在預防登革病毒和做為健康食品設計之運用。
Dengue virus (DV), a flavivirus of Flaviviridae, a positive strand RNA virus with envelope, causes diseases from mild dengue fever to severe dengue hemorrhagic fever and dengue shock syndrome worldwide. The study of WHO showed that dengue virus causes severe infection per year. Limited to different sero-types and antibody-dependent enhancement, there is no effective vaccine for prevention and antiviral agent for therapy of dengue diseases. Therefore, it is noteworthy to find a natural compound for prevention or therapy of dengue virus infection. It is known that blood let-7a was up-regulated in 9-week-old C57BL/6 male mice with feeding honeysuckle (Hs). Does Hs inhibit DV2 infection via let-7a induction? MicroRNAs are on average 22 nt long small RNA molecules. MicroRNAs are able to control viral infection has been reported. It is interesting to identify the microRNA which can inhibit DV2 infection. A Chinese herb honeysuckle (Lonicera japonica; Hs) is generally used to treat wind-heat, sores, and epidemic diseases. Hs also found to inhibit HSV, HIV, RSV, influenza A virus, and SARS. let-7a ,one of up-regulated microRNAs after Hs treatment, was predicted to target DV2 NS1 gene(3313-3333) via Vita website. let-7a induction in blood of 6-day-old suckling mice was stimulated by Hs treatment, indicating that Hs inhibited DV2 replication via let-7a induction. Our study demonstrated that let-7a decreased luciferase activity of the reporter plasmid with DV2 NS1 target sequence. Our Huh7 cell line experiment showed that let-7a inhibited DV2 NS1 RNA (40%) and protein synthesis (20%), as well as DV replication determined by decreased negative strand RNA synthesis. It indicates that let-7a suppressed DV2 replication. In animal studies, Hs pretreatment followed by intracranially inoculated(i.c.) with DV2(2.5 x 105 PFU), showed that Hs delayed disease formation, decreased disease severity. DV2 NS1 RNA (20%) and protein expression (70%), and DV2 titer (45%) was decreased in the brain. In Hs therapy study, mice were i.c. injected with DV2 before feeding Hs. Our data showed that Hs prolonged survival time, delayed disease symptoms, and decreased disease severity of the infected mice. DV2 NS1(78%) and protein expression (52%) , and viral titer (44%) were decreased in mice brain. Above data demonstrated that Hs has an inhibitory effect on DV2 replication. The suckling mice were injected let-7a twice by i.c. after infected with DV2. These showed that let-7a delayed disease formation, reduced DV2 NS1 RNA (26%) and protein expression (50%), and had more than 90% inhibition on viral titer. Above data showed that Hs inhibitory effect on DV replication was related to let-7a stimulation. In conclusion, we are the first to show that honeysuckle can inhibit DV2 infection possibly via let-7a induction. Moreover, let-7a inhibits DV2 replication by directly binding its target site in CDS of DV2 NS1 gene. Our finding may shed light on developing new DV2 prevention and healthy food for dengue virus prevention and therapy.
中文摘要 I
Abstract III
誌謝 V
目錄 VI
導論 1
I. 登革病毒﹙Dengue virus, DV﹚的特徵 1
II. 登革病毒的傳染病學與致病性 2
III. 登革病毒的抑制 3
IV. 微小RNA﹙MicroRNA﹚ 4
V. 微小RNA與病毒間關聯性 6
VI. 微小RNA let-7a之特色 7
VII. 金銀花﹙Lonicera japonica; HS﹚ 7
材料與方法 9
I. 細胞培養(Cell culture) 9
II. 登革病毒之培養(Dengue virus culture) 9
III. 病毒斑分析(Plague assay) 10
IV. 西方墨點法(Western blotting) 11
V. 質體DNA小量製備(Mini-preparation of plasmid DNA) 12
VI. 質體DNA大量製備(Major-preparation of plasmid DNA) 13
VII. 質體之建立(Plasmid construction) 14
VIII. 轉型(Transformation) 15
IX. DNA接合(Ligation) 15
X. 免疫螢光分析法 (IFA) 16
XI. RNA/DNA轉染(RNA/DNA transfection) 17
XII. 冷光酵素活性分析(Luciferase assay) 17
XIII. 細胞存活率分析(MTT assay) 17
XIV. RNA萃取(RNA extraction) 18
XV. 溫度梯度聚合酶連鎖反應(Gradient PCR) 18
XVI. 聚合酶連鎖反應(PCR) 19
XVII. 反轉錄聚合酶連鎖反應 ( RT-PCR ) 20
XVIII. 即時定量聚合酶連鎖反應 ( real-time PCR ) 22
XIX. 動物實驗 23
XX. 統計分析 25
結果 26
I. 金銀花茶誘發仔鼠血液let-7a表現 26
II. 金銀花茶萃取物刺激肝癌Huh7細胞內源性let-7a表現 26
III. let-7a過度表現不會對人類肝癌細胞產生毒性以及在細胞中的穩定性 27
IV. let-7a抑制登革二型病毒複製子﹙D2R2A replicon﹚與pMIR-DV2 NS1 WT等冷光報導基因之活性 27
V. let-7a抑制登革二型病毒的基因和蛋白表現 28
VI. let-7a對登革二型病毒感染有專一性之抑制作用 29
VII. 感染前餵食金銀花茶可延後仔鼠登革病毒感染之病徵產生並減輕疾病嚴重程度 29
VIII. 感染前後餵食金銀花茶能延後仔鼠病徵之出現形成、降低疾病嚴重程度以及降低登革二型病毒基因、蛋白與病毒量 30
IX. 金銀花茶治療受登革病毒感染之仔鼠可延長病鼠存活時間、延後病徵產生並降低疾病嚴重程度 30
X. 金銀花茶治療可減少鼠腦登革二型病毒NS1基因、NS1蛋白表現以及病毒量 ………………………………………………………………………………31
XI. 給予病鼠let-7a能抑制鼠腦內登革二型病毒量 31
討論 33
參考資料 40
Figure 50
Figure 1 Evaluation of let-7a expression level in the blood of the mice after honeysuckle treatment 50
Figure 2 The effect of components extracted from Hs on let-7a expression in Huh7 cells 51
Figure 3 The effect of let-7a on cytotoxicity and stability of hepatoma Huh7 cells 52
Figure 4 The effect of let-7a on luciferase activity of pMIR-DV2-NS1-WT and pMIR-DV2-NS1-Mut reporter plasmid 54
Figure 5 The effect of let-7a on DV2 infection in Huh7 cells 57
Figure 6 The effect of let-7a on different serotype dengue viruses in Huh7 cells 58
Figure 7 The effect of Hs pretreatment on ICR suckling mice challenged with DV2 infection 59
Figure 8 The effect of continuous Hs treatment on ICR suckling mice infected with DV2 infection 61
Figure 9 The effect of honeysuckle on DV2 infection of ICR suckling mice 62
Figure 10 The effect of honeysuckle treatment on ICR suckling mice after DV2 infection 64
Figure 11 The effect of let-7a treatment on ICR suckling mice after DV2 infection 66
Figure 12 The level of endogenous let-7a expression in normal and DV-infected Huh7 cells/mice brain 67

Table 68
Table 1 Summary of the effect of Hs and let-7a treatment on DV2 replication and pathogenesis………………………………………………………………….68
Appendix 69
Appendix 1 let-7a target sequences in DV2 NS1 gene which predicted by Vita website 69
Appendix 2 let-7a target sequence in NS1 gene of DV2 PL046 strain by sequencing 70

簡歷 71

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