人類抗菌胜肽LL-37抑制白色念珠菌貼附之分子機制

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研究生：	蔡裴雯 Tsai, Pei-Wen
論文名稱：	人類抗菌胜肽LL-37抑制白色念珠菌貼附之分子機制 Molecular Mechanisms of Human Antimicrobial Peptide LL-37 Inhibiting Candida albicans Adhesion
指導教授：	藍忠昱 Lan, Chung-Yu
口試委員:	藍忠昱張大慈張壯榮楊程堯羅秀容
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：	2012
畢業學年度：	100
語文別：	英文
論文頁數：	87
中文關鍵詞：	白色念珠菌、貼附
相關次數：	點閱：2 下載：0
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白色念珠菌(C. albicans)為重要的人類伺機性致病真菌之一，其主要存在於人體的黏膜表層，並在免疫力低下的人體造成感染。當白色念珠菌感染時，貼附(adhesion)至宿主的表皮細胞為最重要的第一個步驟。LL-37是一種抗菌胜肽(antimicrobial peptide)，通常扮演免疫系統第一道防線的角色，其存在於各種組織以及包括實驗所用的口腔與泌尿生殖道表皮細胞。首先，我們利用塑膠表面、口腔表皮細胞(OECM-1)與母鼠(BALB/c)膀胱進行白色念珠菌的貼附實驗，結果証實LL-37 可經由抑制白色念珠菌貼附而降低其感染力。我們也觀察到，LL-37透過與白色念珠菌細胞壁之甘露聚糖(mannan)、葡聚糖(glucan)與幾丁質(chitin)結合，而使白色念珠菌凝集(aggregation)，進而抑制白色念珠菌之貼附。此外，我們也發現LL-37能與細胞壁蛋白質Xog1p形成複合物而抑制白色念珠菌貼附至聚苯乙烯(polystyrene)材質表面。
利用噬菌體展示(phage display)與酵素連結免疫吸收(ELISA)實驗，我們找到十個可與LL-37結合的胜肽序列，並從這十個胜肽得到一致序列(consensus sequence)，經由BLAST搜尋比對顯示，有四段胜肽與白色念珠菌細胞壁β-1,3-葡聚糖外切酶(exoglucanase) Xog1p蛋白質上的序列相符。我們以Xog1p蛋白質上第90至第115的胺基酸序列合成一個短胜肽(Xog1p90–115)，並且表現Xog1p的重組蛋白(rXog1p)，結果發現 Xog1p90–115和rXog1p會與LL-37結合，使LL-37失去抑制白色念珠菌貼附的能力。LL-37也會降低白色念珠菌細胞壁Xog1蛋白質活性，因此干擾細胞壁之重組(remodeling)。將白色念珠菌XOG1基因剔除(knock-out)後，細胞葡聚糖外切酶的活性、細胞貼附以及與LL-37結合的能力皆降低，使用白色念珠菌細胞壁Xog1蛋白質的抗體(antibody)也會減少其細胞貼附。因此，藉由LL-37將細胞壁上的糖類(carbohydrate)當做標靶，或其他將Xog1蛋白質當作標靶的化合物，將可能發展為新的藥物，提供防止念珠菌病症的新方法，此外，LL-37也有助於我們篩選其他與真菌細胞貼附相關的細胞壁成分。

Abstract (English) ---------------------------------------------------------------------------- i
Abstract (Chinese) --------------------------------------------------------------------------- ii
Contents ---------------------------------------------------------------------------------------    iii
List of Figures --------------------------------------------------------------------------------    v
List of Tables ---------------------------------------------------------------------------------    vi
Supplementary materials -------------------------------------------------------------------- vii
List of papers published during Ph.D. study --------------------------------------------- viii
Abbreviation ---------------------------------------------------------------------------------- ix

Chapter 1 Introduction---------------------------------------------------------------------    1
1.1    Candida albicans ---------------------------------------------------------------------- 2
1.2    Candida adhesion ---------------------------------------------------------------------    2
1.3    Candida Cell wall --------------------------------------------------------------------- 2
1.4    Candida Xog1p ------------------------------------------------------------------------ 4
1.5    Antimicrobial peptides ---------------------------------------------------------------- 5
1.6    LL-37, an important human AMP --------------------------------------------------- 6
1.7    Specific aims of this study ------------------------------------------------------------ 7

Chapter 2 Materials and Methods ------------------------------------------------------- 9
  2.1 Peptides and reagents ----------------------------------------------------------------- 10
  2.2 C. albicans strains, media, and growth conditions -------------------------------- 10
  2.3 Assays for LL-37 candidacidal activity -------------------------------------------- 12
  2.4 C. albicans adhesion to polystyrene Candida Xog1p ---------------------------- 12
  2.5 Microscopic visualization of floating C. albicans cells--------------------------- 14
  2.6 Assays for LL-37 binding to floating C. albicans cells -------------------------- 14
  2.7 Binding of antimicrobial peptides to C. albicans cells---------------------------- 14
  2.8 Binding of LL-37 to polysaccharides ----------------------------------------------- 15
  2.9 Measurement of dissociation constants for LL-37/mannan complexes -------- 15
  2.10 Adhesion of C. albicans to oral epidermal cells --------------------------------- 16
  2.11 Mouse model for C. albicans adhesion ------------------------------------------- 16
  2.12 CWP extraction and western blotting --------------------------------------------- 17
  2.13 Identification of LL-37-binding proteins by phage-display biopanning ----- 18
  2.14 Characterization of cloned, LL-37-binding phage ------------------------------ 19
  2.15 Searching for the potential LL-37 interacting proteins from Candida
      Genome Database (CGD) ---------------------------------------------------------- 20
  2.16 ELISA for LL-37 /Xog190–115 association ---------------------------------------- 21
  2.17 Expression, purification, and refolding of recombinant Xog1p --------------- 21
  2.18 Preparation and purification of polyclonal antibodies against C. albicans
      Xog1p --------------------------------------------------------------------------------- 22
  2.19 Interaction of LL-37 and rXog1p ------------------------------------------------- 23
  2.20 Glucanase activity assay -----------------------------------------------------------    24
  2.21 Cell susceptibility to agents that interrupt cell-wall integrity ----------------- 24
  2.22 Construction of C. albicans mutant strains and Southern blotting ----------- 25
  2.23 RNA isolation and reverse transcriptase-PCR ----------------------------------    26
  2.24 Statistical analysis ------------------------------------------------------------------ 27
  2.25 Accession numbers of XOG1 and EXG2 sequences --------------------------- 27

Chapter 3 Results -------------------------------------------------------------------------- 28
Part I Human Antimicrobial Peptide LL-37 Inhibits Adhesion of Candida
     albicans by interacting with Yeast Cell-Wall Carbohydrates --------------- 29
  3.1 LL-37 kills C. albicans ----------------------------------------------------------- 30
  3.2 LL-37 affects adhesion of C. albicans to polystyrene ------------------------ 30
  3.3 LL-37 induces cell aggregation and reduces cell attachment to
       polystyrene by directly binding to C. albicans ------------------------------- 31
   3.4 LL-37 binds to C. albicans cell-wall polysaccharides and thereby
       reduces C. albicans adhesion --------------------------------------------------- 33
    3.5 Effects of LL-37 on C. albicans adhesion to oral epidermal cells
       and the urinary bladders of mice ----------------------------------------------- 35
Part II Characterizing the Role of Cell-Wall β -1,3-Exoglucanase Xog1p in
      Candida albicans Adhesion by the Human Antimicrobial Peptide
      LL-37 ----------------------------------------------------------------------------- 45
    3.6 Binding of LL-37 to C. albicans CWPs -------------------------------------- 46
    3.7 Xog1p: an LL-37-binding target identified by phage-display
       biopanning ------------------------------------------------------------------------ 46
    3.8 LL-37 associates with Xog1p -------------------------------------------------- 47
    3.9 Roles of Xog1p in LL-37-mediated inhibition of C. albicans
       adhesion --------------------------------------------------------------------------- 48
    3.10 Xog1p is involved in C. albicans adhesion --------------------------------- 49

Chapter 4 Discussion --------------------------------------------------------------------- 61
Chapter 5 Conclusion and future perspectives ------------------------------------- 68
References ---------------------------------------------------------------------------------- 71
Supplementary Materials --------------------------------------------------------------- 80

List of Figures

Figure 1 Layer structure of fungal cell wall -------------------------------------------- 3
Figure 2 Structure of Xog1p -------------------------------------------------------------- 4
Figure 3 Sequence of the human cathelicidin ------------------------------------------- 7
Figure 4 Helical wheel diagram of LL-37 ----------------------------------------------- 7
Figure I-1 Candidacidal activity of LL-37 ---------------------------------------------- 37
Figure I-2 Adhesion of LL-37-treated cells to polypropylene centrifugation
         tubes ---------------------------------------------------------------------------- 38
Figure I-3 Inhibition of C. albicans adhesion by LL-37 ------------------------------ 39
Figure I-4 LL-37-induced C. albicans cell aggregation and LL-37 binding to
         C. albicans --------------------------------------------------------------------- 40
Figure I-5 The inhibition of cell adhesion caused by LL-37 is the result of
         peptide-cell binding and cell-cell aggregation ---------------------------- 41
Figure I-6 Binding of LL-37 to Candida cell-wall polysaccharides reduces
         Candida adhesion to polystyrene ------------------------------------------- 43
Figure I-7 LL-37 inhibits C. albicans attachment to oral epidermal cells and
         mouse bladder mucosa ------------------------------------------------------- 44
Figure II-1 Binding of LL-37 to C. albicans cell-wall proteins ---------------------- 52
Figure II-2 Identification of potential LL-37-binding peptides by phage
         display -------------------------------------------------------------------------- 53
Figure II-3 Expression of full-length Xog1p and its interaction with LL-37 ------- 54
Figure II-4 Xog1p plays a role in LL-37-mediated inhibition of C. albicans
         adhesion ------------------------------------------------------------------------ 55
Figure II-5 XOG1 deletion reduces C. albicans adhesion to polystyrene and
         decreases cell association with LL-37 -------------------------------------- 57
Figure II-6 EXG2 has no significant effect on C. albicans cell adhesion or
         cellular interaction with LL-37 ---------------------------------------------- 59
Figure II-7 Xog1p plays a role in the adhesion of C. albicans to polystyrene ------ 60










List of Tables

Table 1 Potential limitations of antimicrobial peptides development ---------------- 5
Table 2 Strains of Candida albicans used in this study -------------------------------- 11
Table 3 Properties of AMPs used in this study ------------------------------------------ 32

































Supplementary Materials

Figure S1 LL-37 binding to Candida was examined by immunohistochemistry --- 81
Figure S2 Flow cytometric analysis of LL-37 binding to C. albicans cells --------- 82
Figure S3 The Xog1p90-112 is exposed on structural surface --------------------------- 83
Figure S4 ELISA analysis of the interaction between rXog1p and LL-37 ----------- 84
Figure S5 One of the LL-37 binding proteins was Xog1 which soluble form
         could compete the effects of LL-37 ------------------------------------------ 85
Figure S6 XOG1 mutant strains attach to urinary bladders of mice ------------------- 86
Figure S7 The sequence alignment of Xog1p and Exg2p ------------------------------- 87

                                

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