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研究生：	李威廷 Lee, Wei-Ting
論文名稱：	氧化鐵奈米粒子阻止艱難梭狀桿菌之孢子發芽並減緩艱難梭狀桿菌: 體外及活體系統之機制與療效探討 Iron Oxide Nanocrystals Prohibit Clostridium difficile Spore Germination and Attenuate Intestinal Inflammation: an in vitro and in vivo Mechanistic and Therapeutic Investigation
指導教授：	蔡佩珍 Tsai, Pei-Jane 謝達斌 Shieh, Dar-Bin
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：	2017
畢業學年度：	105
語文別：	英文
論文頁數：	104
中文關鍵詞：	艱難梭狀桿菌感染、胞子、奈米粒子、活體實驗
外文關鍵詞：	Clostridium difficile Infection, Spores, Nanoparticles, in vivo test
相關次數：	點閱：131 下載：2
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艱難梭狀桿菌為可形成內孢子細菌，導致世界各地與住院相關的腹瀉，並也是個嚴重的重複感染原。其感染之臨床控制仍然未臻理想，主因在該菌體的孢子型態能對抗許多化學藥劑及物理性途徑之傷害。另一方面，已有相當多類型的奈米粒子被證明具有抗微生物功能，甚至能對付多重抗藥性細菌。然而大多該類型研究鮮少論及奈米粒子對宿主細胞的生物相容性及對正常微生物叢的影響。我們的研究發現隨著四氧化三鐵奈米粒子濃度愈高，其抑制艱難梭狀桿菌發芽的效果愈佳。其效果與次氯酸鈉之正向對照組相近。藉由管餵方式給予小鼠艱難梭狀桿菌孢子所建立的動物感染模式研究顯示受感染之對照組小鼠較經過四氧化三鐵奈米粒子治療實驗組小鼠，其腸道發炎嚴重度高約三倍。組織病理分析結果顯示對照組感染鼠之大腸組織有大量嗜中性白血球浸潤，而經四氧化三鐵奈米粒子處理過的實驗組則有顯著較少嗜中性白血球。在四氧化三鐵奈米粒子導致的艱難梭狀桿菌孢子萌發抑制機制方面的探討，減少吡啶二羧酸從胞子釋放而阻擋了孢子後續之萌發程序。經活體實驗結果證明，四氧化三鐵奈米粒子在沒有明顯造成小鼠治療副作用的負面影響下，具有顯著減緩艱難梭狀桿菌引起的發炎反應之療效。而由體外實驗則證明，此奈米粒子亦能延緩艱難梭狀桿菌形成孢子的時間。綜合整個研究結果，我們歸結四氧化三鐵奈米粒子具有發展為預防及治療艱難梭狀桿菌感染之全新型製劑的潛力。

Clostridium difficile, a spore forming bacterium, is the leading cause of hospital-acquired diarrhea and serious re-emerging pathogen worldwide. Clinical management of C. difficile infection is still far from satisfactory as its spores are resistant to many chemical and physical treatments. Certain types of nanoparticles exhibit anti-microbial efficacy even in multi-drug resistance bacteria. However, only few of these studies addressed the biocompatibility issues to the host and the normal flora. This study identified an octahedron iron oxide nanocrystal, Fe3-δO4, capable of inhibiting spore germination close to that of the sodium hypochlorite. In a C. difficile infection animal model, the inflammatory level tripled in mice with colonic C. difficile spores compared to the group with the Fe3-δO4 nanoparticles co-treatment. Histopathological analysis showed an intense neutrophil accumulation in the colon tissue of the negative control-group mice but not in the nanoparticle-treated mice. The Fe3-δO4 nanoparticles reduced the dipicolinic acid release thus effectively block spores germination. These results suggested that the Fe3-δO4 nanoparticles, which had no apparent side effects in vivo, were efficacious inhibitors of C. difficile spore germination. In addition, the Fe3-δO4 nanoparticles attenuated C. difficile induced inflammation in mice and delayed sporulation in the in vitro test. Therefore, the Fe3-δO4 nanoparticles possess great potential as a new class of effective C. difficile prophylaxis and therapeutic strategy.

Contents
Abstract I
中文摘要 II
Acknowledgements III
Contents IV
Figure contents	VIII
Table contents XI
Abbreviations XII
Introduction 1
1 C. difficile infection 1
2 C. difficile spores	3
3 Anti-C. difficile spore studies 5
4 Nanomaterials 6
5 Antibacterial activity of nanomaterials 7
Objective and Specific Aims 10
1 Objective 10
2 Specific aims 10
Materials and Methods 12
1 Incubating bacteria and purifying spores 12
2 Spore staining 13
3 Preparing the nanoparticles	13
4 Spore germination test using optical density 600 nm detection 15
5 Spores germination test using phase-contrast microscopy 17
6 Spore viability assay 17
7 Spore binding assay 18
8 Cryo-electron tomography video 18
9 Trans-electron microscopic analysis of spores 18
10 DPA release determination 19
11 Cell viability assay 20
12 The effect of the Fe3-δO4 nanoparticles on animal colon 20
13 The Fe3-δO4 nanoparticles circulation in mice 21
14 The effect of the Fe3-δO4 nanoparticles on kidney and liver function in mice 21
15 The effect of the Fe3-δO4 nanoparticles on guts microbiota 22
16 The viability of gut common bacteria test	22
17 C. difficile infection in vivo determination 23
18 Inflammatory gene expression test 24
19 Histopathological analysis	24
20 The therapeutic efficacy assay of the Fe3-δO4 nanoparticles against CDI 25
21 The sporulation test of C. difficile 25
22 Statistical analysis 26
Results 27
1 The Fe3-δO4 nanoparticles presented the ability of anti-spore germination against C. difficile. 27
2 The Fe3-δO4 nanoparticles blocked the transformation of spores via morphological studies. 28
3 Inhibitory effect of the Fe3-δO4 nanoparticles on virulent strains of C. difficile and B. subtilis. 30
4 The Fe3-δO4 nanoparticles could not decrease the viability of C. difficile vegetative cells. 31
5 The mechanisms underlying the Fe3-δO4-inhibited spore germination. 31
6 The Fe3-δO4 nanoparticles demonstrated their good biocompatibility. 33
7 The Fe3-δO4 nanoparticles as an in vivo sporicidal agent against C. difficile infection. 35
8 The Fe3-δO4 nanoparticles could be a therapeutic reagent for C. difficile infection. 36
9 The Fe3-δO4 nanoparticles retarded sporulation of C. difficile. 36
Discussion 38
1 Nanotechnology could be a strategy for anti-spores. 38
2 Sporulation is a critical weak spot for C. difficile therapeutic design. 40
3 The Fe3-δO4 nanoparticles negatively affect C. difficile spores germination in vitro and the postulated mechanisms. 41
4 The Fe3-δO4 nanoparticles has high efficacy in the control of C. difficile infection in vivo. 44
5 The Fe3-δO4 nanoparticles have cross-strain efficacy for C. difficile spores and B. subtilis spores germination. 45
6 The Fe3-δO4 nanoparticles is safe for C. difficile spore elimination. 46
7 Some thoughts about future development of the Fe3-δO4 nanoparticles in infectious disease managements. 49
Conclusion 51
References 52
Figure 68
Tables 103


                                    

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