白色念珠菌Aro1影響細胞壁完整性、生物膜形成及致病性之研究

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研究生：	葉英傑 Yeh, Ying-Chieh
論文名稱：	白色念珠菌Aro1影響細胞壁完整性、生物膜形成及致病性之研究 Influence of Candida albicans Aro1 on cell wall integrity, biofilm formation and virulence
指導教授：	藍忠昱 Lan, Chung-Yu 傅化文 Fu, Hua-Wen
口試委員:	高茂傑 Kao, Mou-Chieh 謝家慶 Shieh, Jia-Ching 賴志河 Lai, Chih-Ho
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 分子與細胞生物研究所 Institute of Molecular and Cellular Biology
論文出版年：	2018
畢業學年度：	106
語文別：	英文
論文頁數：	73
中文關鍵詞：	白色念珠菌、Aro1 、細胞壁、生物膜、致病性
外文關鍵詞：	Candida albicans, Aro1, cell wall, biofilm, virulence
相關次數：	點閱：2 下載：0
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白色念珠菌是一種伺機性病原菌，能夠引起表淺性甚至致命性的全身感染。白色念珠菌ARO1基因編譯一種arom多功能酵素，可能參與莽草酸路徑的催化反應以合成芳香族胺基酸。這個合成路徑存在於真菌卻不存在哺乳類中，代表Aro1是個發展抗菌藥物具有吸引力的目標。然而，白色念珠菌的Aro1功能至今還沒被探討。在此，我們顯示ARO1基因降低菌株顯現的生長缺陷可藉由補充芳香族胺基酸來回復。此外，ARO1基因降低菌株容易聚集並沉澱。而這些ARO1基因降低也會造成細胞壁特性與組成改變，並促進白色念珠菌細胞貼附到聚苯乙烯與生物膜形成。再者，我們的結果指出ARO1基因降低會影響白色念珠菌與表皮細胞之間的交互作用並造成宿主細胞損傷。最後，ARO1基因降低菌株也顯示出其毒性下降。總結來說，這個研究對於未來治療白色念珠菌提供代謝與毒性上全新觀點。

Candida albicans is an opportunistic pathogen capable of causing superficial infections to life-threatening systemic infections. The C. albicans ARO1 gene encodes an arom multifunctional enzyme, which can catalyze reactions of the shikimate pathway to synthesize aromatic amino acids. This pathway exists in fungi but not in mammals, representing an attractive target for antifungal drug development. However, the functions of C. albicans Aro1 have not been characterized. Here, we showed that defective growth in the ARO1-knockdown strain was rescued by supplemental aromatic amino acids. In addition, the ARO1-knockdown strain was easily aggregated and precipitated. The knockdown of ARO1 also caused changes in properties and compositions of cell wall and promoted cell adhesion to polystyrene and biofilm formation in C. albicans. Moreover, our results indicate that ARO1 knockdown affects the interaction between C. albicans and epidermal cells and causes host cell damage. Finally, the ARO1-knockdown strain showed attenuation of C. albicans virulence. Together, this work sheds new insights into nutrient metabolism, cell wall and virulence of C. albicans.

Abstract..........................................................I
中文摘要..........................................................II
致謝辭...........................................................III
Table of Contents................................................IV
List of Tables...................................................VI
List of Figures.................................................VII
Abbreviation...................................................VIII
Chapter 1: Introduction...........................................1
1.1 Candida albicans and Candida infection........................2
1.2 Nutrient metabolism is important for C. albicans virulence and pathogenicity.....................................................2
1.3 The cell wall of C. albicans..................................3
1.4 Cell wall integrity and Mitogen-activated protein kinase (MAPK) in C. albicans....................................................5
1.5 The AROM enzyme in biosynthesis of aromatic amino acids.......5
1.6 The aims of this study........................................6
Chapter 2: Materials and Methods..................................8
2.1 C. albicans strains, medium and growth conditions.............9
2.2 Construction of the C. albicans mutant strain carrying heterozygous deletion of ARO1.....................................9
2.3 Construction of the tetracycline-regulatable C. albicans strains..........................................................10
2.4 Flocculation and sedimentation of C. albicans cells..........11
2.5 Cell surface hydrophobicity (CSH) assay......................11
2.6 Cell susceptibility to cell wall-perturbing agents...........12
2.7 Measuring cell wall carbohydrate content.....................12
2.8 RNA preparation and reverse transcription (RT) real-time quantitative PCR (qPCR)..........................................13
2.9 Protein extraction and western blot..........................14
2.10 C. albicans adhesion to polystyrene and biofilm formation...14
2.11 C. albicans adhesion to epidermal cells.....................16
2.12 Lactate dehydrogenase assay.................................16
2.13 Virulence assay.............................................17
2.14 Determining the exposure of β-(1,3)-glucan on the cell wall.17
Chapter 3: Results...............................................19
3.1 C. albicans orf19.4704 is a homolog of S. cerevisiae Aro1....20
3.2 C. albicans Aro1 is involved in the synthesis of aromatic amino acids............................................................20
3.3 ARO1 knockdown induces cell aggregation and sedimentation....21
3.4 C. albicans ARO1 is related to cell wall integrity...........21
3.5 ARO1 knockdown affects cell wall integrity through activation of the Mkc1 signaling pathway....................................23
3.6 ARO1 affects cell adhesion and biofilm formation.............23
3.7 C. albicans ARO1 knockdown promotes adhesion to human epithelioid cells and triggers cell damage.......................24
3.8 ARO1 knockdown attenuates C. albicans virulence..............25
Chapter 4: Discussion............................................27
Chapter 5: Future Prospects......................................32
5.1 Is ARO1 related to the TOR signaling pathway?................33
5.2 How importance is Aro1 in septum formation?..................33
5.3 How does ARO1 knockdown strain secrete more extracellular matrix (ECM) in the biofilm?.....................................34
5.4 Whether nutrient signaling is correlated with antifungal drug susceptibility of C. albicans?...................................34
Chapter 6: References............................................36
Tables and Figures...............................................48
Publication List.................................................73
                                

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