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系統識別號 U0026-2408201423280400
論文名稱(中文) 內皮細胞中對抗A群鏈球菌的細胞自噬機制缺失原因:含有細菌的細胞自噬體之酸化缺失
論文名稱(英文) The mechanism behind inefficient group A streptococcus clearance by autophagy in endothelial cells: defective acidification of bacteria-containing autophagosomes
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 102
學期 2
出版年 103
研究生(中文) 呂女秀菱
研究生(英文) Shiou-Ling Lu
學號 S58961387
學位類別 博士
語文別 英文
論文頁數 88頁
口試委員 指導教授-林以行
口試委員-吳俊忠
召集委員-莊偉哲
口試委員-吉森保
口試委員-郭志峰
口試委員-安德森羅伯
中文關鍵字 A群鏈球菌  細胞自噬  內皮細胞  酸化作用 
英文關鍵字 group A Streptococcus  autophagy  endothelial cells  acidification 
學科別分類
中文摘要 化膿性鏈球菌,又名為A群鏈球菌,為人類重要感染致病菌,其疾病嚴重程度與細菌和血管接觸及擴散相關,如造成嚴重的菌血症和多重器官衰竭。雖然此菌可以進入非吞噬型的細胞,進而逃脫免疫監控和抗生素毒殺,過去報導指出,進入上皮細胞內的A群鏈球菌會誘發細胞自噬,使其在溶小體融合的細胞自噬體中被有效率的清除。本研究結果顯示,不同M蛋白血清型的A群鏈球菌菌株在內皮細胞可存活與生長。而細菌增生倍數和臨床疾病嚴重程度呈現正相關,但與M蛋白血清型則無相關性。細菌持續在細胞中生長最後造成內皮細胞走向如同壞死性的細胞死亡。為了找出內皮細胞無法有效清除A群鏈球菌的原因,我們著重於觀察感染後早期的狀態。結果發現酸性培養液的前處理,可降低細菌在內皮細胞中生長的能力。然而,若細胞中無法持續提供酸性環境,例如以bafilomycin A1處理抑制細胞中的所有酸化作用,酸前處理過的細菌則可以在內皮細胞中再次複製生長。觀察細菌無法生長在其中的上皮細胞,發現細胞自噬體結構能維持完整酸化環境,得以抑制細菌,然而,可能是由於內皮細胞的細胞自噬體形成缺失的關係,導致細菌所在環境即使已有溶小體融合,仍然沒有辦法維持在低pH值的狀態,使得細菌在內皮細胞內生長不受抑制。對於上皮細胞能夠經由細胞自噬清除細菌的能力,也因為bafilomycin A1的處理抑制酸化作用而消失。總結以上研究結果,我們發現酸化是上皮細胞透過細胞自噬有效率抑制A群鏈球菌生長的重要因子。然而相對的,在內皮細胞中,酸性環境無法維持,而造成A群鏈球菌在內皮細胞中存活並複製生長。
英文摘要 Streptococcus pyogenes (Group A Streptococcus, GAS) is an important human pathogen and its interaction with blood vessels is critically important in serious events such as bacteremia or multi-organ failure. GAS may internalize into non-phagocytic cells which provide a strategy to escape from immune surveillance and antibiotic killing. However, GAS has also been reported to induce autophagy and is efficiently killed within lysosome-fused autophagosomes in epithelial cells. In the present study, we found that different M serotypes of GAS strains can survive and grow in endothelial cells. The ability of GAS to replicate is related to the clinical symptom severity but not the M serotype. GAS growth causes endothelial cells to undergo a necrotic-like cell death. To investigate the mechanism of insufficient GAS clearance in endothelial cells, we focus on the early stage of infection. Bacterial replication can be suppressed by inactivating GAS in an acidic medium before internalization into endothelial cells, and this inhibitory effect can be reversed by treatment with bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase. As compared with epithelial cells in which acidification causes autophagy-mediated clearance of GAS, there was a defect in acidification of GAS-containing vesicles in endothelial cells. Low pH is consequently not maintained in GAS-containing autophagosomes in endothelial cells, thereby resulting in GAS replication inside LAMP-1 and LC3 positive vesicles. Furthermore, treatment of epithelial cells with bafilomycin A1 resulted in defective GAS clearance by autophagy, with subsequent bacterial growth intracellularly. Taken together, low pH is a key factor for autophagy-mediated suppression of GAS growth inside epithelial cells, while defective acidification of GAS-containing vesicles results in bacterial growth in endothelial cells.
論文目次 Abstract……………………………………………………………………………….I
Chinese abstract……………………………………………………………………..II
Acknowledgment……………………………………………………………….......III
Table content………………………………………………………………………..IV
Figure list…………………………………………………………………………. VII
Abbreviations……………………………………………………………………..VIII
Introduction
Group A Streptococcus………………………………………………………………..1
Virulence factors..………………………………………………………...............1
Endotoxins..………………………………………………………………….2
Exotoxins..…………………………………………………………………...2
Virulence factors inside GAS………………………………………………..3
Pathogenesis and clinical symptoms……………………………………………...4
Treatment and prevention………………………………………………………...4
Autophagy……………………………………………………………………………..5
Selective autophagy formation……………………………………………………5
Lysosomes…………….…………………………………………………………..7
Acidification………………………………………………………………………8
GAS-induced autophagy………………………………………………………….8
Interaction between current GAS and host cells………………………………………9
Objective and specific aims………………………………………………………...11
Materials and methods
Materials
Cells..……………………………………………………………………….12
Bacteria……………………………………………………………………..12
Methods
Cell culture………………………………………………………………….13
Bacterial culture…………………………………………………………….13
Infection model…………………………………………………………......14
Immunofluorescence staining………………………………………………14
Transfection………………………………………………………………...15
Flow cytometry analysis for intracellular GAS growth…………………….15
Cell death assay….……………………………………………………….....15
Western blot………………………………………………………………...16
pH detection………………………………………………………………...16
Generation of Atg knockdown HMEC-1 cells……………………………...16
Immunohistochemistry staining…………………………………………….17
Statistical analysis…………………………………………………………..18
Results
Replication of GAS with different M serotypes in endothelial cells……………19
The clinical relevance of GAS growth between non-invasive and invasive diseases…………………………………………………………………………..19
Non-invasive GAS strain SF370 can not grow and may be cleared by autophagy in HMEC-1 cells………………………………………………………………...20
The role of autophagy for invasive GAS infection in endothelial cells…………20
GAS multiplication occurs outside autophagosome…………………………….21
GAS growth causes endothelial cells to undergo a necrotic-like cell death…….22
Low pH affects GAS growth in culture broth…………………………………...23
Low pH affects GAS growth in endothelial cells……………………………….24
Fusion of lysosomes with autophagosomes……………………………………..25
Loss of acidic pH in GAS-containing vesicles in endothelial cells……………..25
GAS replicates inside LC3- or LAMP-1-positive vesicles in endothelial cells…26
Low pH is required for suppression of GAS intracellular growth………………26
GAS localizes to endothelium in vivo…………………………………………...27
Discussion
Bacterial diversity……………………………………………………………….28
Environmental effects…………………………..……………………………….29
The dual role of low pH for host lysosomal activity and bacterial suppression...30
Cell type diversity……………………………………………………………….30
Selective autophagy……………………………………………………………..32
Possible mechanisms underlying deficient GAS-induced autophagosome formation in endothelial cells
Deficiency of ubiquitination…………………………………………...33
Deficiency of 8-nitro-cGMP-mediated ubiquitination on GAS..………34
Deficiency of autophagosome formation……………………………....34
Other possible mechanisms behind the loss of low pH in GAS-containing vesicles in endothelial cells……………………………………………………………….35
The localization of GAS inside non-phagocyte in vivo…………………………36
Conclusion…………………………………………………………………………...38
References…………………………………………………………………………...39
Figures and figure legends………………………………………………………….51
Appendixes…………………………………………………………………………..75
1. The growth of GAS in Atg5 or Atg7 knockdown HMEC-1 cells……………75
2. Low pH affects GAS virulence factor gene expression………………...........76
3. Acid-pretreated GAS displays limited growth in lysosome in endothelial cells…………………………………………………………………………77
4. Drugs, reagents, kits, antibodies, consumables, instruments………………...78
Publications………………………………………………………………………….83
Curriculum Vitae…………………………………………………………………...85
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