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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/19336完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 王錦堂(Jin-Town Wang) | |
| dc.contributor.author | Yi-Yin Chen | en |
| dc.contributor.author | 陳依吟 | zh_TW |
| dc.date.accessioned | 2021-06-08T01:54:18Z | - |
| dc.date.copyright | 2016-08-26 | |
| dc.date.issued | 2016 | |
| dc.date.submitted | 2016-07-15 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/19336 | - |
| dc.description.abstract | 抵抗吞噬細胞的吞噬作用為結核桿菌屬的細菌最主要的致病機制，故本研究利用海洋分支桿菌 (M. marinum) 作為研究材料。海洋分支桿菌是結核分支桿菌的近親，其基因體定序已被完成，在魚類造成的病症和人類結核病相類似，接著再以黏菌 (Dictyostelium discoideum) 作為宿主模式。黏菌和哺乳類巨噬細胞有許多相似的特徵，具有吞噬並殺死細菌的能力，可用來替代研究致病菌與巨噬細胞之間的交互作用，成為快速篩選的實驗平台。本研究利用跳躍子建立了1728株海洋分支桿菌突變株庫，並篩選出對黏菌具有毒力的基因。篩選後獲得30株突變株仍可使黏菌存活，此30株突變株共分別影響20個基因區段，其中有6個基因 (losA, mmar_2318, mmar_2319, wecE, mmar_2323 and mmar_2353) 位於脂寡聚醣 (lipooligosaccharide/LOS) 生合成區段中。脂寡聚醣為已知細胞壁上的醣脂抗原，在海洋分支桿菌中主要的脂寡聚醣結構為LOS-I到LOS-IV四種。
以二維色層薄層分析法 (2D-TLC) 分析醣脂抗原，結果發現mmar_2318 和 mmar_2319的基因剔除株皆為LOS-III累積量提高而LOS-IV生成缺失，其基因剔除株與基因補回株皆證實mmar_2318 和 mmar_2319會對黏菌造成毒力，但不顯著影響細菌進入黏菌的比例以及細菌在黏菌內複製的能力。進一步利用鼠類巨噬細胞株(J774a.1)及人類巨噬細胞株 (PMA-induced THP-1) 進行實驗，結果發現mmar_2318 和 mmar_2319的基因剔除株，其在細胞株內的複製能力皆不受影響，但細菌進入細胞的比例在THP-1中有顯著增加，而J774a.1則否。總結來說，雖然mmar_2319已有研究指出會參與LOS的生合成，但我們仍發現了新的基因，mmar_2318並且一樣參與LOS的生合成路徑，且mmar_2318 與mmar_2319的基因剔除株會降低對黏菌的毒力作用並細菌增加進入THP-1的細菌數。 | zh_TW |
| dc.description.abstract | Resistance to phagocyte killing is an important virulence factor in mycobacteria. Dictyostelium has been used to study the interaction between phagocytes and bacteria, given its similarity to the mammalian macrophage. Here, we investigated the genes responsible for virulence to Dictyostelium by screening 1728 transposon mutants of the Mycobacterium marinum NTUH-M6094 strain. A total of 30 mutants that were permissive for Dictyostelium growth were identified. These mutants revealed interruptions in 20 distinct loci. Of the 20 loci, six genes (losA, mmar_2318, mmar_2319, wecE, mmar_2323 and mmar_2353) were located in the lipooligosaccharide (LOS) synthesis cluster. LOS are antigenic glycolipids and the core LOS structure from LOS-I to LOS-IV have been reported to exist in M. marinum. Two-dimensional thin-layer chromatography (2D-TLC) glycolipid profiles revealed that deletion of mmar_2318 or mmar_2319 resulted in the accumulation of LOS-III and deficiency of LOS-IV. Deletion and complementation of mmar_2318 or mmar_2319 confirmed that both genes contributed to virulence towards Dictyostelium but not entry and replication inside Dictyostelium. Co-incubation with a murine macrophage cell line J774a.1 or PMA-induced human monocytic cell line THP-1 demonstrated that mmar_2318 or mmar_2319 deletion mutant could grow in macrophages, and their initial entry rate was not affected in J774a.1 but significantly increased in THP-1. In conclusion, although mmar_2319 has been reported to involve LOS biosynthesis in a previous study, we identified a new gene, mmar_2318 that is also involved in the biosynthesis of LOS. Deletion of mmar_2318 or mmar_2319 both exhibits reduction of virulence towards Dictyostelium and increased entry into THP-1 cells. | en |
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| dc.description.tableofcontents | 目錄
口試委員會審定書 I 致謝 II 中文摘要 III ABSTRACT IV 第一章 緒論 1 結核病與結核桿菌 1 人類結核分支桿菌的致病機制 1 海洋分支桿菌 2 黏菌 2 黏菌模式應用於細菌研究 3 分支桿菌的細胞壁脂寡聚醣 4 第二章 研究目的 6 第三章 材料與方法 7 菌株培養方法、載體與引子序列 7 LB 培養液 7 7H9 培養液 7 7H11培養基 7 HL5培養液 8 建構海洋分支桿菌基因突變株庫 8 放大帶有跳躍子的噬菌體 8 測定噬菌體濃度 9 利用phAE94建構NTUH-M6094的基因突變株庫 9 篩選出海洋分支桿菌基因突變庫中對黏菌具有毒力的基因 9 黏菌吞噬斑突變株庫篩選實驗方法 10 突變株序列分析 11 第一次半隨機聚合酶連鎖反應條件 11 第二次半隨機聚合酶連鎖反應條件 12 基因剔除株的建構 13 載體的建構 13 分支桿菌勝任細胞的製備 14 載體的送入與基因剔除株建立 14 基因補回株的建立 15 海洋分支桿菌的脂質層萃取及分析 15 脂質層萃取 15 二維薄層色層分析 (two-dimensional thin layer chromatography / 2D-TLC) 16 以海洋分支桿菌感染黏菌 [52] 17 以海洋分支桿菌或人類結核桿菌感染巨噬細胞[39] 17 第四章 實驗結果 20 建構海洋分支桿菌的突變株庫 20 篩選突變株庫中可使黏菌存活的突變株 20 海洋分支桿菌脂寡聚醣的二維薄層色層分析 21 mmar_2318與mmar_2319基因剔除株與基因補回株的表型確認 22 生長能力的差異 22 吞噬斑的確認 22 菌落型態與菌落大小 23 mmar_2318與mmar_2319對黏菌的感染 23 第五章 討論與總結 26 突變株庫的代表性 26 利用黏菌模式篩選之結果 27 mmar_2318與mmar_2319對脂寡聚醣的生合成 28 mmar_2318與mmar_2319對黏菌的毒殺 29 mmar_2318與mmar_2319與巨噬細胞 29 mmar_2318與mmar_2319的基因相似度 30 巨噬細胞與黏菌差異 31 總結 32 第六章 參考文獻 33 第七章 延伸實驗 (Mycobacterium tuberculosis H37Rv) 40 實驗目的： 40 實驗結果： 40 人類結核桿菌基因剔除株對人類巨噬細胞的感染 40 人類結核桿菌基因剔除株對人類巨噬細胞的細胞毒力 41 人類結核桿菌基因剔除株脂質層的二維薄層色層分析 41 實驗討論： 42 參考文獻 43 表目錄 表一、 實驗中海洋分支桿菌所使用的載體與引子序列 45 表二、 實驗中人類結核桿菌所使用的引子序列 46 表三、17株隨機挑選的突變株經半隨機聚合酶連鎖反應後的定序結果 47 表四、跳躍子突變株庫中可使黏菌存活的突變株 48 圖目錄 圖一. 添加微量產氣克雷伯氏桿菌(Klebsiella aerogenes)可於海洋分枝桿菌的跳躍子突變株庫中篩選出失去對黏菌具有毒力(virulence)作用的突變株。 49 圖二、跳躍子嵌入海洋分支桿菌脂寡聚醣生合成基因區段中的詳細嵌入位置 50 圖三、海洋分支桿菌mmar_2318與mmar_2319基因剔除株以及基因補回株的基因排列與脂寡聚醣二維薄層色層分析 51 圖四、海洋分支桿菌losA、wecE與mmar_2353跳躍子突變株的脂寡聚醣二維薄層色層分析 52 圖五、海洋分支桿菌野生株、2318以及2319基因剔除株在33oC與20oC培養溫度下的生長曲線圖。 53 圖六、mmar_2318與mmar_2319基因剔除株與基因補回株的表型確認I-黏菌吞噬斑的形成 54 圖七、mmar_2318與mmar_2319基因剔除株與基因補回株的表型確認II-吞噬斑的定量分析 55 圖八、mmar_2318與mmar_2319基因剔除株與基因補回株的表型確認III-菌落型態與大小 56 圖九、mmar_2318與mmar_2319基因剔除株進入黏菌胞內數目與存活率 57 圖十、mmar_2318與mmar_2319基因剔除株進入巨噬細胞內數目與存活率 58 附錄 附錄一、 半隨機聚合酶連鎖反應(Semi-random PCR)的實驗原理。 60 附錄二、.利用重覆區段聚合酶連鎖反應(overlap PCR)建構無標記基因剔除載體(unmarked deletion vector)。 61 附錄三、pGOAL19 62 附錄四、人類結核桿菌基因剔除株進入巨噬細胞內數目與存活率 63 附錄五、人類結核桿菌基因剔除株對人類巨噬細胞的毒性 64 附錄六、人類分枝桿菌野生株，1502與1524突變株的細胞壁脂質層二維薄層色層分析 65 | |
| dc.language.iso | zh-TW | |
| dc.title | 海洋分支桿菌mmar_2318和mmar_2319基因負責生合成細胞壁脂寡聚醣與調控對黏菌的毒性 | zh_TW |
| dc.title | Mycobacterium marinum mmar_2318 and mmar_2319 are Responsible for Lipooligosaccharide Biosynthesis and Virulence towards Dictyostelium: screening in a transposon mutant library | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 104-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 賴信志(Hsin-Chih Lai),楊宏志(Hung-Chih Yang),蔡丰喬(Feng-Chiao Tsai),張永祺(Yung-Chiy Chang) | |
| dc.subject.keyword | 海洋分支桿菌,脂寡聚醣,致病力,巨噬細胞,黏菌, | zh_TW |
| dc.subject.keyword | M. marinum,lipooligosaccharide,virulence,macrophage,Dictyostelium, | en |
| dc.relation.page | 65 | |
| dc.identifier.doi | 10.6342/NTU201600926 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2016-07-15 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 微生物學研究所 | zh_TW |
| 顯示於系所單位： | 微生物學科所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-105-1.pdf 未授權公開取用 | 2.32 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。