白色念珠菌是人體常見的正常共生真菌，經常存在於一般健康人體的皮膚及黏膜表面。然而，白色念珠菌也是一種伺機性致病菌，可造成表淺型或甚至全身系統性感染，尤其對免疫力低下的患者造成嚴重威脅。在黏膜及植入性醫療器材上形成生物膜是白色念珠菌毒力及致病的相關特徵之一，生物膜的形成並且與白色念珠菌的抗藥性及對人體免疫系統的抵禦都非常相關。本研究中，我們主要研究白色念珠菌在形成生物膜新的調節機制，發現轉錄因子Rap1參與調控白色念珠菌之細胞壁完整性、生物膜生成及毒力。研究結果顯現RAP1基因剔除的菌株展現比野生菌株有更高生物膜形成的能力，其原因可能是由於生物膜基質之增加。此外，RAP1剔除菌株的細胞壁醣類成分與Mkc1和Cek1活化皆有增加的現象。最後，我們也以Galleria mellonella 幼蟲做為全身系統性感染的模式，發現RAP1基因剔除減弱了白色念珠菌的毒力。據我們所知，這是第一份發現Rap1參與白色念珠菌細胞壁、生物膜的形成和毒力的研究報告。

Candida albicans is a member of human microflora and commonly inhabits the skin and mucosal surfaces of healthy individuals without any harm. However, C. albicans is also an opportunistic pathogen that can cause a range of infections including superficial candidiasis and life-threatening systemic candidemia, particularly in the immunocompromised patients. One of the important features related to C. albicans virulence and pathogenesis is its ability to form biofilm on the mucosa or implanted medical devices. Moreover, biofilm is also closely related to antifungal resistance and fungal escape from human immune defense. In this study, we revealed new mechanisms in regulation of C. albicans biofilm formation. Our results indicated that the transcription factor Rap1 contributes to cell well integrity (CWI), biofilm formation, and virulence. The deletion of RAP1 enhanced biofilm formation compared to the WT and RAP1-reintegrated strains, possibly through enhancing the extracellular matrix. In addition, the rap1-deletion mutant showed an increase in cell wall glycan contents and Mkc1 and Cek1 activation. Finally, the rap1-deleted mutant attenuated C. albicans virulence in a Galleria mellonella systemic infection model. To our knowledge, this is the first report to show that Rap1 involves in C. albicans cell wall, biofilm formation and virulence.

中文摘要................................................................................................................................... I
Abstract...................................................................................................................................II
致謝辭..........................................................................................................................Ⅲ
1. Introduction..........................................................................................................1
1.1 Infections caused by Candida species and fitness attributes and virulence factors of C. albicans .............................................................................................2
1.2 Drug resistance and biofilm formation of C. albicans.....................................3
(1) Emergence of antifungal resistance in C. albicans ..................................3
(2) Biofilm formation in C. albicans infections and drug resistance.............4
1.3 The cell wall of C. albicans .............................................................................5
(1) The composition and architecture of the cell wall ...................................5
(2) The cell wall integrity signaling pathway ................................................6
1.4 The transcription factor Rap1 ..........................................................................7
2. Materials and Methods ....................................................................................8
2.1 C. albicans strains and growth conditions .......................................................9
2.2 Measurement of cell adhesion and biofilm formation .....................................9
2.3 Examination of C. albicans biofilm and extracellular matrix using scanning electron microscopy (SEM) .................................................................................10
2.4 Cell susceptibility to cell wall-perturbing agents...........................................10
2.5 Cell surface hydrophobicity (CSH) assay......................................................11
2.6 Measurement of carbohydrate content in the cell wall ..................................11
(1) Measurement of the total cell-wall carbohydrates .................................11
(2) Measurement of the content of the individual cell-wall carbohydrates .12
2.7 Calcofluor white staining for cell wall chitin ................................................13
2.8 RNA preparation and reverse transcription (RT) real-time quantitative PCR (qPCR) .................................................................................................................13
2.9 Biofilm matrix isolation.................................................................................14 2.10 Protein extraction and protein quantification...............................................14 2.11 Western blot .................................................................................................15 2.12 Examination of the hyphal formation ..........................................................15
2.13 Biofilm antifungal susceptibility assay........................................................15 2.14 Determining the β-glucan exposure on the cell wall ...................................16 2.15 Virulence assay using the Galleria mellonella model .................................16
2.16 Statistical analysis........................................................................................17
3. Results ..................................................................................................................18
3.1 C. albicans Rap1 is involved in biofilm formation........................................19
3.2 Rap1 also affects cell wall integrity...............................................................20
3.3 Rap1 affects cell wall integrity through the Mkc1 and Cek1 MAPK pathways..............................................................................................................................21
3.4 The adhesion ability of the rap1-deletion is dispensable in biofilm formation..............................................................................................................................22
3.5 The filamentation of the rap1-deletion is dispensable in biofilm formation .22
3.6 The biofilm of the rap1-deletion mutant shows an increase in extracellular matrix ...................................................................................................................23
3.7 The biofilm of the rap1-deletion is more resistant to antifungal drug than the controls.................................................................................................................23
3.8 The rap1-deletion mutant attenuates C. albicans virulence ..........................24
4. Discussion............................................................................................................26
5. References ...........................................................................................................30
Tables.........................................................................................................................38
Table 1. Strains used in this study ....................................................................38
Table 2. Oligonucleotides used in this study....................................................39
Figures.......................................................................................................................40
Fig. 1. Deletion of RAP1 enhances C. albicans biofilm formation. ....................41
Fig. 2. Deletion of RAP1 changes the cell wall integrity. ....................................42
Fig. 3. The rap1-deletion increased the cell wall polysaccharides with the cell wall defect............................................................................................................43
Fig. 4. Activation of the cell wall integrity signaling pathways in the rap1-deleted mutant......................................................................................................44
Fig. 5. The adhesion is not the key to affect the increased biofilm formation in the rap1-deletion mutant......................................................................................45
Fig. 6. The rap1-deletion mutant exhibits a normal filamentous growth. ...........46
Fig. 7. Deletion of RAP1 enhances C. albicans extracellular-matrix secretion in biofilm formation.................................................................................................48
Fig. 8. The biofilms of the rap1-deletion mutant are more tolerance to fluconazole than the control strains. ....................................................................49
Fig. 9. Deletion of RAP1 enhances β-1,3-glucan exposure and attenuates C. albicans virulence. ...............................................................................................51
Supplementary Figures.......................................................................................52
Fig. S1. The gene expressions of chitin synthase are mediated by the CWI pathway................................................................................................................53
Fig. S2. The gene expressions of glucan synthase are mediated by the CWI pathway................................................................................................................54

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