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研究生(外文):Chen, Ruei-Ching
論文名稱:探討人類抗菌胜肽hepcidin 25於白色念珠菌之作用機制
論文名稱(外文):Studying modes of action of human antimicrobial peptide hepcidin 25 against Candida albicans
指導教授(外文):Lan, Chung-Yu
口試委員(外文):Wang, Horng-DarKao, Mou-ChiehShieh, Jia-ChingChen, Ying-Lien
中文關鍵詞:白色念珠菌抗菌胜肽hepcidin 25
外文關鍵詞:Candida albicansantimicrobial peptidehepcidin 25
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人類Hepcidin 25 (hep 25) 是富含半胱胺酸由25個胺基酸組成的抗菌胜肽,並含有一個與銅/鎳金屬結合的ATCUN 模組 (motif)。本研究主要在於探討此胜肽對白色念珠菌之作用機制。在研究的第一部分,結果顯示hep 25 具有廣效的殺菌能力,可以有效對抗包含氟康唑耐藥性的白色念珠菌與其他念珠菌屬的臨床分離菌株,而且與抗壞血酸有協同殺菌作用。此外,ATCUN 模組不僅有助於活性氧類的產生,並且參與hep 25的殺菌力。另外,hep 25 會造成粒線體的活性氧類與鈣離子過度累積,降低粒線體膜電位。最後,hep 25也會造成半胱氨酸蛋白酶活化,細胞膜的磷脂醯絲氨酸外翻及DNA斷裂,這都顯示hep 25會誘導細胞凋亡。在第二部分的研究指出,hep 25 殺菌作用是具有能量依賴性的,而非透過破壞細胞膜的結構與改變細胞壁的完整性。使用細胞內吞作用抑制劑、內吞及其他缺陷之突變菌株等,進一步顯示內吞機制與銅離子分佈皆與hep 25的殺菌作用相關。本研究不僅有助於了解含有ATCUN 模組的抗菌胜肽,也提供未來開發此類抗真菌藥物之可能性。
Human hepcidin 25 (hep 25) is a 25-amino acid cysteine-rich antimicrobial peptide, and also contains the amino-terminal Cu(II)/Ni(II)-binding (ATCUN) motif. The main goal of this thesis is to study modes of action for hep 25 against Candida albicans. In the first part of this study, hep 25 was shown to have a broad-spectrum microbicidal activity against many strains including clinical isolates of fluconazole-resistant C. albicans and other Candida species, and possess a synergistic candidacidal activity with ascorbic acid. Moreover, the ATCUN motif of hep 25 not only involves in ROS production but also contributes to candidacidal activity of the peptide. Additionally, hep 25 causes mitochondrial reactive oxygen species (ROS) accumulation, calcium overload and decreased mitochondrial membrane potential. Finally, hep 25 induces many characteristics of apoptosis such as metacaspase activation, phosphatidylserine (PS) exposure and DNA fragmentation. In the second part of this study, the killing activity of hep25 is energy-dependent without membrane lytic activity and alteration of cell wall integrity. Using various endocytosis inhibitors and C. albicans mutant strains defective in endocytosis and other cellular processes, these results further indicated that endocytosis and copper distribution are associated with killing activity of hep 25. Together, this thesis reveals the mode of action for the ATCUN-containing peptides, and provides insights for future development of new antifungal agents.
中文摘要 I
Abstract II
致謝辭 III
Contents V
List of Tables X
List of Figures XI
Chapter 1 Introduction 1
1.1 The Candida species and Candida albicans 2
1.2 Antimicrobial peptides (AMPs) 3
1.3 Human hepcidin 5
1.3.2 Function of hep 25 8 Regulation of human iron homeostasis 8 Antimicrobial activity 9 DNA cleavage activity 10
1.4 Apoptosis 10
1.5 Clustered regularly interspaced short palindromic repeats (CRISPR) system for gene deletion in C. albicans 11
1.6 Aims of this study 12
Chapter 2 Materials and Methods 14
2.1 Peptides and regents 15
2.2 Strains and growth condition 15
2.3 Cell susceptibility to hep 25 16
2.3.1 Minimum fungicidal concentration (MFC) assay 16
2.3.2 CFU counting assay 17
2.3.3 Propidium iodide (PI) staining 17
2.4 Liposome calcein leakage assay 17
2.4.1 Preparation of SUVs mimicking cell membrane of C. albicans and containing calcein 18
2.4.2 Calcein leakage assay 18
2.5 Determination of subcellular localization of hep 25-GGK-FITC 19
2.6 Measurement of intracellular ROS accumulation 19
2.7 Measurement of mitochondrial membrane potential (ΔΨm) 19
2.8 Measurement of mitochondrial calcium level 20
2.9 Metacaspase activity assay 20
2.10 Annexin V-FITC and PI co-staining assay 21
2.11 Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay 21
2.12 Statistical analysis 22
Chapter 3 Results 23
Part I:Hep 25 induces Candida albicans apoptosis 24
3.1 Concentration and pH-dependent candidacidal activity of hep 25 25
3.2 Candidacidal activity of hep 25 in Candida clinical isolates 26
3.3 Hep 25 induces intracellular ROS accumulation 26
3.4 The ATCUN motif of hep 25 is involved in ROS production and correlated with the activity of hep 25 27
3.5 Hep 25 alters mitochondrial potential and calcium homeostasis 28
3.6 Mitochondrial metabolic state also affects cell susceptibility to hep 25 29
3.7 Hep 25 induces metacaspase activation 30
3.8 Hep 25 induces phosphatidylserine (PS) externalization and DNA fragmentation 31
Part II:Energy-dependent endocytosis is linked to the fungicidal activity of hep 25 against C. albicans 57
3.8 Hep 25 kills C. albicans without changing its cell wall and cell membrane integrity 58
3.10 The candidacidal activity of hep 25 is energy-dependent 59
3.11 Endocytosis process is correlated with the candidacidal activity of hep 25 60
3.12 Deletion of the low-affinity copper transporter Ctr2, but not the CTR1-null mutant, is supersensitive to hep 25 60
Chapter 4 Discussion and Future Perspectives 69
4.1 Part I: Hep 25 induces C. albicans cells apoptosis 70
4.1.1 The candidacidal activity of hep 25 70
4.1.2 The ATCUN motif and the candidacidal activity of hep 25 71
4.1.3 Mitochondrial ROS production is also related to the candidacidal activity of hep 25 72
4.1.4 Hep 25 causes mitochondrial dysfunction and apoptosis 73
4.2 Part II: Energy-dependent endocytosis is linked to the fungicidal activity of hep 25 against C. albicans 75
4.2.1 The association of hep 25 and C. albicans cell surface 75
4.2.2 Hep 25 gains entry into C. albicans cells through endocytosis 75
4.2.3 Copper homeostasis, intracellular trafficking and hep 25 76
4.3 Future perspectives 78
4.3.1 To assessment of the potential synergistic effects of hep 25 78
4.3.2 Modulation of candidacidal activity of hep 25 mediated by copper 79
4.3.3 To reveal the mechanisms of endocytosis and intracellular trafficking of hep 25 80
Chapter 5 References 93
Chapter 6 Additional studies: using the CRISPR/Cas9 system to generate the CTR1-null mutant 106
6. 1 The CRISPR system for C. albicans gene editing 107
6. 2 The detailed protocol for generation of C. albicans CTR1-null mutant 107
6.2.1 To generate the Cas9-sgCtr1RNA expression cassette (Step 1 in Figure 34) 107
6.2.2 Design of the repair template primers and generation of the repair template by overlap extension PCR (Step 2 in Figure 34) 108
6.2.3 Co-transformation of the Cas9-sgCTR1RNA and the repair template into C. albicans (Step 3 and 4 in Figure 34) 109
6.2.4 Validation of the correct insertion of the Cas9-sgCtr1RNA and the repair template in C. albicans genome (Step 5 in Figure 34) 110
6.2.5 Cassette pop-out through FLP-mediated homologous recombination and allele specific PCR (Step 6 and 7 in Figure 34) 112
6.2.6 Phenotypic characterization of CTR1-null mutant constructed using the CRISPR/CaCas9 system (Step 8 and 9 in Figure 34) 113
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