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研究生:鄭曲真
研究生(外文):Chu-Chen Cheng
論文名稱:於動物模式研究抗登革病毒非結構性蛋白1抗體
論文名稱(外文):Study on the pathological effects of anti-dengue virus nonstructural protein 1 antibodies in the animal model
指導教授:林以行
指導教授(外文):Yee- Shin Lin
學位類別:碩士
校院名稱:國立成功大學
系所名稱:微生物暨免疫學研究所
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:2001
畢業學年度:90
語文別:中文
論文頁數:62
中文關鍵詞:登革病毒非結構性蛋白1動物模式
外文關鍵詞:Dengue virusnonstructural proteinanimal model
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在分類學上隸屬於黃熱病毒科的登革病毒 (在血清學上則存在著登革1到4型) 乃是經由蚊子為媒介而傳染。而受到登革病毒感染的病患,其所產生的臨床症狀也常會有程度上的差異,依其病況的不同,我們可將其區分為具有輕微發燒症狀登革熱及可能危及生命的出血性登革熱 (DHF) 及登革休克反應 (DSS)。而受到登革病毒感染的病患,血中的aspartate aminotransferase (AST) 和alanine aminotransferase (ALT) 這兩種肝臟的轉胺脢會有升高的情形。我們在之前的研究中觀察到,在受到登革病毒感染的病患及登革非結構性蛋白1 (NS1) 免疫小鼠的血清中存在高量的anti-NS1抗體,且發現anti-NS1抗體會與內皮細胞及血小板產生反應。考慮到疫苗設計的安全性,anti-NS1抗體的存在是否會有不良的影響,例如造成血管通透性的增加以及肝臟和腎臟的傷害,便是我們有興趣去研究的。C3H/HeN小鼠分別以重組的登革病毒NS1或做為對照組的日本腦炎NS1蛋白免疫1次、3次或5次,並偵測其產生的anti-NS1 IgG及IgM抗體。在免疫過3及5次的小鼠體內可以偵測到高效價的anti-NS1 IgG抗體,而高效價的anti-NS1 IgM抗體在免疫過5次的小鼠體內亦可觀察到。此外, 和以日本腦炎NS1蛋白免疫的小鼠比較,在登革病毒NS1免疫的小鼠體內,可以觀察到肝臟轉胺脢上升的情形,尤其以AST最為明顯,但是blood urea nitrogen (BUN) 的含量並沒有變化。由NS1免疫小鼠的病理切片中發現,小鼠的肝臟有受損的情形,尤其是那些AST明顯上升的小鼠,但是所有小鼠的腎臟組織切片皆呈現正常的結果,並無任何病理現象產生。此外,在登革熱的病理研究方面,血管的漏損 (vascular leakage) 是和DHF/DSS有關的臨床症狀。皮下注射anti-NS1抗體到BALB/c小鼠體內,我們發現到anti-NS1抗體會在小鼠體內造成血管通透性的增加。總言之,由本研究之動物模式顯示anti-NS1抗體的產生,在登革病毒感染造成的病理現象中可能扮演著重要的角色。

Dengue viruses (DV; serotypes 1 to 4) belonging to the Flaviviridae are mosquito-born virus. Patients with dengue virus infection show a wide range of clinical effects, from mild fever to life-threatening symptoms of hemorrhagic fever and/or shock syndrome (DHF/DSS). Elevation of liver enzymes including aspartate aminotransferase (AST) and alanine aminotransferase (ALT) could be observed in dengue virus-infected patients. In previous studies, the anti-dengue virus nonstructural protein 1 (NS1) antibodies present in patient and immune murine sera were detected, and their reactivities with endothelial cells and platelets were demonstrated. For the safety concern of vaccine development, whether anti-NS1 antibodies may cause harmful effects, such as increase in vascular permeability, and hepatic and renal injury, are of interest for investigation. C3H/HeN mice were immunized with recombinant DV NS1 or Japanese encephalitis virus (JEV) NS1 as a control for one, three, or five times, and the anti-NS1 IgG and IgM were determined. High titers of anti-NS1 IgG were detected after injection with NS1 for 3 or 5 times. Anti-NS1 IgM could also be detected with a highest level after 5-time injection of NS1. Elevated levels of liver enzymes, especially the AST, could be detected in DV NS1 hyper-immune sera as compared to JEV NS1 hyper-immune sera, but the change of BUN was not observed. Gross and histological examination of NS1 hyper-immunized C3H/HeN mice revealed tissue damage in livers, especially in mice which had higher AST, but all histological examination of kidneys appeared normal without evidence of pathology. Moreover, in dengue pathology, the vascular leakage is one of the clinical features associated with DHF/DSS. Using subcutaneous injection of anti-NS1 antibodies into BALB/c mice, the anti-NS1 antibodies caused an increase in the permeability of mouse vessel in vivo. Taken together, studies in the animal model of this project indicated that the generation of anti-NS1 antibodies may play a role in the pathogenesis of dengue virus infection.

中文摘要……………………………………………………………………….…I
英文摘要……………………………………………………………………..….III
致謝…………………………………………………………………….…….…..V
目錄………………………………………………………………………….….VI
圖目錄……………………………………………………………………….….IX
表目錄……………………………………………………………………….…..X
附錄目錄…………………………………………………………………….….XI
符號及縮寫索引表…………………………………………………….………XII
第一章、序論…………………………………………………………….….…...1
第二章、材料與方法……………………………………………………...…..…7
I.材料……………………………………………………….…..…..…...7
A.實驗動物…………………………………………………………..…7
B.細菌株……………………………………………………………..…7
C.試劑與材料…………………………………………………….….…8
D.抗體…………………………………………………..….…..………11
E.儀器………………………………………………….….………...…11
F.耗材……………………………………………………….…………13
II.方法………………………………………………………….………..16
A.NS1重組蛋白的製備………………………………....…….………16
A.1 NS1重組蛋白的誘導表現……………………....…….……..16
A.2 NS1重組蛋白的純化…………………………...……..……..16
B.SDS-PAGE膠體電泳…………………………………..…..….……17
B.1 SDS-PAGE膠體電泳步驟…………………………….….…..17
B.2 以細菌為待測樣本的處理……………………………..….....18
C.蛋白質定量……………………………………………………..…...18
D.NS1重組蛋白免疫小鼠及血清的製備…………………….…..…..18
E.酵素結合免疫吸附法(Enzyme-linked immunosorbent assay﹔ELISA)測定抗體的濃度…………………………………….…………...…..19
E.1以DV或JEV NS1重組蛋白免疫小鼠血清為一級抗體.…....20
F.抗體的製備及前處理……………………………….…………...…..20
F.1抗體的純化………………………………………..….….….….20
F.2 FITC conjugated anti-NS1 IgG……………………….…....…....21
G.血清中生化成份的測定……………………………….….……..…..22
H.器官的病理變化……………………………………….….….….…..22
H.1組織切片的製備………………………………….….….…..….22
H.2以HE stain觀察器官的病理變化……………….….……...….22
I.觀察血管通透性的改變……………………………….….……..…..23
I.1.1 polyclonal anti-NS1 antibody…………………….……..….….23
I.1.2 control antibody………………………………………..….…...23
I.2利用染料擴散觀察血管通透性的改變………………...….……23
第三章、結果…………………………………………………………....….……..24
A. NS1重組蛋白的產生………………………………………….….….24
B.NS1免疫小鼠的血清中含有高效價的抗NS1抗體………….…....25
C.免疫小鼠血清中AST、ALT的偵測………………………….…….25
D.免疫小鼠血清中BUN的偵測…………………………………...….26
E.免疫小鼠肝臟的病理變化……………………………….…….…....27
F.免疫小鼠腎臟的病理變化………………………………….….…..27
G.Anti-NS1抗體對小鼠血管通透性的影響…………………….…..28
第四章、討論…………………………………………………………….….….29
參考文獻………………………………………………………………….….….34
圖………………………………………………………………………….….….43
附錄……………………………………………………………………….….….55
作者簡歷
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