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系統識別號 U0026-0105202021270800
論文名稱(中文) 菸鹼醯胺嘌呤雙核苷酸恆定性於A群鏈球菌存活於血管內皮細胞內角色
論文名稱(英文) The role of NAD+ homeostasis in the group A streptococcal survival within endothelial cells
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 108
學期 2
出版年 109
研究生(中文) 謝承陸
研究生(英文) Cheng-Lu Hsieh
學號 S58001226
學位類別 博士
語文別 英文
論文頁數 143頁
口試委員 指導教授-吳俊忠
召集委員-鄧景浩
口試委員-林以行
口試委員-蔡佩珍
口試委員-郭志峯
口試委員-江倪全
中文關鍵字 A群鏈球菌  血管內皮細胞  菸鹼醯胺  菸鹼醯胺嘌呤雙核苷酸恆定性  細胞內存活  自噬作用 
英文關鍵字 Group A Streptococcus  Endothelial cells  Nicotinamide  NAD+ homeostasis  Intracellular survival  Autophagy 
學科別分類
中文摘要 A群鏈球菌(又名為化膿性鏈球菌)是一種人類致病菌,其會導致輕微之咽喉炎,乃致嚴重之壞死性筋膜炎。過去的研究認為A群鏈球菌是胞外致病菌,近年來的研究指出A群鏈球菌可入侵細胞,藉以躲避宿主免疫系統攻擊與抗生素作用。然而,A群鏈球菌是如何躲避細胞內清除的機制仍需進一步探討。最近許多研究指出細菌的菸鹼醯胺嘌呤雙核苷酸核苷酶(NADase)與細胞能量平衡和細菌在宿主細胞內存活相關聯。本論文主要探討A群鏈球菌NADase如何在人類血管內皮細胞中存活的機制。首先,血管內皮細胞(HMEC-1)與NADase突變株(SW957)感染模式顯示,NADase對於A群鏈球菌在內皮細胞內生長相當重要,其會導致細胞內菸鹼醯胺嘌呤雙核苷酸(NAD+)含量降低。共軛焦顯微鏡結果亦顯示,雖然野生株(NZ131)與NADase突變株(SW957)在內皮細胞內皆會被細胞自噬作用捕捉,但僅有含突變株的自噬小體會被溶酶體有效酸化。這結果暗示著,NADase會消耗細胞內NAD+含量,並抑制溶酶體介導的酸化作用,導致A群鏈球菌可在內皮細胞中增殖。隨後,在細胞培養液額外添加菸鹼醯胺(nicotinamide,NAM)的環境下,深入探討NAD+恆定性與A群鏈球菌在內皮細胞內存活的關聯性。結果顯示當逐步添加NAM於細胞培養液中,可以抑制A群鏈球菌在內皮細胞內生長。而且當內皮細胞處理NAM後,可提高細胞內NAD+的含量,並提高細胞的存活率。過去研究指出,細胞內NAD+會調節細胞自噬作用,因此以慢病毒方式將細胞自噬相關蛋白質之基因(ATG9A)剔除後,顯示在缺乏ATG9A基因的人類血管內皮細胞中,NAM無法有效抑制A群鏈球菌在內皮細胞生長;共軛焦顯微鏡結果也顯示,額外添加NAM會誘導細胞自噬作用,並促進溶酶體介導的酸化作用,藉此達到抑制A群鏈球菌在內皮細胞中的生長。然而,額外添加NAM並無法有效抑制抗甲氧苯青黴素金黃葡萄球菌(methicillin-resistant Staphylococcus aureus)、李斯特氏菌(Listeria monocytogenes)以及鼠沙門氏桿菌(Salmonella Typhimurium)在內皮細胞中的生長。這些結果顯示,NAD+恆定性對於A群鏈球菌於血管內皮細胞中之存活機制扮演著重要角色。目前臨床上以抗生素治療A群鏈球菌的主軸外,本研究提供以NAD+機制為基礎,提供對抗A群鏈球菌感染的新型治療策略。
英文摘要 Group A Streptococcus (Streptococcus pyogenes, GAS) is a versatile pathogen that causes a wide spectrum of diseases from mild pharyngitis to life-threatening necrotizing fasciitis. Invading host cells is a strategy for GAS to avoid antibiotic killing and immune system clearance. However, the underlying mechanisms of GAS resistance to intracellular clearance have not been yet understood. NAD-glycohydrolase (NADase) has been shown to involve in intracellular energy balance and bacterial survival within host cells. In this study, the human endothelial HMEC-1 cells were infected with GAS to assess the contribution of NAD+ in GAS growth. Firstly, the endothelial cells infected with NADase-knockout SW957 were the subjects to measure the intracellular NAD+ level change and to evaluate the intracellular bacterial growth by confocal microscopy and colony-forming assay. The results showed that the NADase activity was closely associated with the growth of GAS in the endothelial cells. Moreover, the intracellular levels of NAD+ and the ratio of NAD+/NADH in the wild-type NZ131-infected HMEC-1 cells were lower than that of the NADase-knockout SW957-infected cells. Although both NZ131 and its isogenic NADase-knockout mutant were trapped into the LC3-positive autophagosomes, only the vacuoles containing the NADase-knockout mutants were highly co-localized with the acidified lysosomes. These results indicate that NADase hydrolyses intracellular NAD+ content and prevents the acidification of autophagosomes, thus promotes GAS growth in the endothelial cells. Secondly, the correlation of NAD+ homeostasis and nicotinamide (NAM) supplement for GAS survival in the endothelial cells was investigated. The results showed that the growth of intracellular GAS was greatly inhibited by treatment with exogenous NAM. In the NAM-treated cells, the NAD+ content and the NAD+/NADH ratio were significantly increased, resulting in an enhancement of cell viability. Nonetheless, autophagy has been known to be regulated by intracellular NAD+ level and NAD+/NADH ratio. After the knockdown of the autophagy-related gene ATG9A, the number of intracellular bacteria was increased in the NAM-treated endothelial cells. Confocal microscopic graphs of NZ131-infected HMEC-1 cells revealed an increased percentage of GAS-containing autophagosomes that co-localized with lysosomes under NAM-supplemented conditions. However, in a parallel experiment, NAM-supplementation did not effectively inhibit the growth of methicillin-resistant Staphylococcus aureus, Listeria monocytogenes, and Salmonella Typhimurium in the endothelial cells. Taken together, these results have demonstrated that the homeostasis of the intracellular NAD+ in endothelial cells is crucial for GAS survival from autophagy. The conclusion derived from this study has provided a fundamental work to develop a new therapeutic strategy to cope with persistent GAS infections.
論文目次 中文摘要.....I
Abstract.....III
Acknowledgement.....V
Table of Contents.....VI
List of Tables.....XII
List of Figures.....XIII
List of Appendix Figures.....XV

Introduction.....1
General characterization of Streptococcus pyogenes.....1
Infection and epidemiology.....1
Treatment.....3
General steps of GAS pathogenesis.....4
Adhesion and colonization.....4
Invasion and intracellular survival.....4
Evasion of immune responses.....5
Autophagy.....5
Characterization of virulence factors of GAS.....7
M protein.....8
Streptococcal pyrogenic exotoxin B (SpeB).....9
Streptolysin.....11
NADase.....12
The regulation of virulence genes in GAS.....14
NAD+ homeostasis.....15
The aims of this study.....16

Material and Method.....18
Bacterial strains and culture conditions.....18
Cell line and cell culture conditions.....19
Animals.....19
Construction of isogenic mutants.....20
NADase-knockout mutant.....20
NADase G330D mutant.....21
SLO mutant.....22
Streptococcus genomic DNA preparation.....22
Plasmid DNA extraction.....23
E. coli.....23
GAS.....24
Competent cell preparation for heat-shock transformation.....24
Heat-shock transformation.....25
Competent cell preparation of for electroporation of GAS.....25
Electroporation for GAS.....26
Bacterial stock preparation for nature transformation of Streptococcus gordonii.....26
Competent cell preparation and nature transformation.....27
Southern hybridization.....27
Genomic DNA digestion and electrophoresis.....27
DNA treatment and transfer.....28
Probe preparation.....28
DNA hybridization.....29
Measurement of NADase activity.....29
Intracellular bacteria survival analysis.....30
NAD+ quantification.....31
MTS cell viability assay.....31
Cell cytotoxicity assay.....32
Measurements of intracellular reactive oxygen species (ROS) level.....32
RNA interference.....33
Western blotting.....34
Protein sample preparation.....34
SDS-PAGE electrophoresis and Western blot.....34
Transmission electron microscopy (TEM).....35
Confocal microscopy.....36
Statistical analysis.....37

Results.....38
NADase contributes to GAS survival in endothelial cells.....38
The NADase activity is required for GAS growth in endothelial cells.....38
Residue 330 of NADase contributes to GAS survival in endothelial cells.....39
NADase depletes intracellular NAD+ content to result in cell death.....40
NADase prevents GAS-containing vacuoles maturation in endothelial cells.....41
The intracellular growth of GAS is decreased in nicotinamide (NAM)-treated endothelial cells.....43
Nicotinamide elevates intracellular NAD+ content and the NAD+/NADH ratio of endothelial cells.....44
Given exogenous nicotinamide can reduce cell death and reactive oxygen species production during GAS infection.....45
Autophagy is activated by nicotinamide to inhibit GAS growth in endothelial cells.....46
Nicotinamide increases the maturation of GAS-containing autophagosomes in endothelial cells.....48
Nicotinamide specifically inhibits intracellular GAS growth in endothelial cells.....49
Nicotinamide treatment can alleviate the skin damage, but not the mortality in GAS-infected mice.....50

Discussion.....52
The microvascular endothelium is involved in the GAS survival intracellularly.....52
NADase is require for GAS survival in the host cells.....53
NAD+ homeostasis is associated with GAS survival in the host cells.....54
Autophagy is regulated by NAD+ homeostasis to mediate intracellular GAS survival.....57
The maturation of autophagosome is depending on the intracellular NAD+ level.....59
NAD+ homeostasis is a specific mechanism for bacterial survival in the host cells.....60

References.....63
Tables.....91
Figures.....96
Appendix.....125
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