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研究生：	吳彥萱 Wu, Yen-Hsuan
論文名稱：	探討金黃色葡萄球菌殺白細胞毒素Luekocidin AB對於嗜中性白血球的致病性 New insights into the role of leukocidin AB in the pathogenesis of Staphylococcus aureus in neutrophil
指導教授：	齊嘉鈺 Chi, Chia-Yu
學位類別：	碩士 Master
系所名稱：	醫學院 - 微生物及免疫學研究所 Department of Microbiology & Immunology
論文出版年：	2023
畢業學年度：	111
語文別：	英文
論文頁數：	117
中文關鍵詞：	金黃色葡萄球菌、殺白細胞素AB 、多形核白血球、NLRP3發炎小體、嗜中性白血球胞外誘捕網、細胞壞死
外文關鍵詞：	Staphylococcus aureus, leukocidin AB, polymorphonuclear neutrophils, NLRP3 inflammasome, neutrophil extracellular traps, necrosis
相關次數：	點閱：77 下載：0
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金黃色葡萄球菌（Staphylococcus aureus）分泌多種細胞外毒素以損害不同的宿主細胞，進而導致相當多樣性的疾病。最新鑑定出的金黃色葡萄球菌成孔殺白細胞素AB （LukAB），對於包括多形核白血球（polymorphonuclear neutrophils, PMNs）在內的多種免疫細胞具有毒性。此外，過去的研究也指出LukAB會促進免疫細胞產生免疫反應，包含導致巨噬細胞中NLRP3發炎小體的活化，進而引發細胞焦亡，以及促進PMNs釋放嗜中性白血球胞外誘捕網 (Neutrophil extracellular traps, NETs)。然而，LukAB是否造成PMNs中的發炎小體活化，以及LukAB所誘導NETs釋出的機制尚不清楚。在本研究中，我們使用已知會表現LukAB的金黃色葡萄球菌株，包含USA300和B56778，以及同源的LukAB剔除突變株和其衍生的LukAB回補株分別感染人類PMNs，以評估LukAB對於PMNs的致病機制。結果顯示，不論感染之金黃色葡萄球菌是否表現LukAB，造成PMNs細胞內NLRP3發炎小體相關分子，包含caspase-1、gasdermin D (GSDMD)，以及介白素-1β (interleukin-1β，IL-1β)的活化程度相當。然而，僅有表現LukAB的菌株所感染的PMNs才會大量釋放IL-1β，並伴隨細胞死亡；進一步的研究證實，該種細胞死亡與細胞焦亡有所不同；LukAB破壞PMNs的細胞膜導致細胞壞死性死亡。此外，我們發現不論感染PMNs之金黃色葡萄球菌是否表達LukAB，皆會造成與發炎小體相關的GSDMD活化而形成NETs。然而，只有表達LukAB的菌株會促進NETs由PMNs中釋放。綜上所述，我們的結果顯示LukAB在PMNs細胞膜上形成孔洞的能力觸發了壞死性細胞死亡快速發生，同時伴隨著IL-1β和NETs從PMNs當中釋放。這些發現對於金黃色葡萄球菌感染期間，LukAB的致病機制以及其所造成的PMNs免疫反應提供了新見解。

Staphylococcus aureus produces an array of extracellular toxins that damage host cells, leading to a wide spectrum of diseases. Leukocidin AB (LukAB), a recently identified bi-component pore-forming leukotoxin of S. aureus, is cytotoxic to immune cells including polymorphonuclear neutrophils (PMNs). Moreover, LukAB has been demonstrated to elaborate the immune response by promoting NLRP3 inflammasome activation and pyroptosis in macrophages, as well as neutrophil extracellular traps (NETs) extrusion in PMNs. However, the role of LukAB in inflammasome activation in PMNs and the underlying mechanism of LukAB-induced NETs remain unknown. In this study, we used LukAB-expressing S. aureus strains, USA300 and B56778, together with isogenic lukAB deletion mutants and complemented strains to evaluate the involvement of LukAB in PMN pathogenesis. The results showed comparable activation of NLRP3 inflammasome molecules, including caspase-1, gasdermin D (GSDMD), and IL-1β, in PMNs infected with S. aureus regardless of the presence or absence of LukAB. However, the release of IL-1β and cell death were observed only in the presence of LukAB, which was distinct from pyroptosis; LukAB disrupted the cell membrane of PMNs, leading to necrotic cell death. We also showed that GSDMD maturation, associated with inflammasome activation, played a role in NETs formation in PMNs infected with all S. aureus strains. However, only LukAB-expressing S. aureus strains promoted NETs extrusion. Taken together, our results suggested that the pore-forming ability of LukAB triggered a rapid necrosis, accompanied by the release of IL-1β and extrusion of NETs from PMNs. These findings provide insights into the pathogenic mechanisms of LukAB and its impact on the immune responses of PMNs during S. aureus infections.

中文摘要 I
Abstract II
誌謝 III
Contents IV
List of Tables IX
List of Figures X
List of Appendix XI
Chapter 1. Introduction 1
1. Staphylococcus aureus 1
1.1. The Diseases and Pandemic of S. aureus 1
1.2. Methicillin-Resistant S. aureus (MRSA) 1
1.3. Alternative Therapeutic Strategy 2
2. Virulence Factors 2
2.1. Diversity of S. aureus Virulence Factors 2
2.2. Leukocidins 3
2.3. Leukocidin AB 4
3. Polymorphonuclear Neutrophils (PMNs) 5
3.1. Functions 5
3.2. Inflammasome Activation 5
3.3. Neutrophil Extracellular Traps 7
4. Rationale and Specific Aim 8
Chapter 2. Materials and Methods 10
1. Materials 10
1.1. Whole Blood Samples 10
1.2. Bacterial Strains 10
1.3. Plasmids 10
1.4. Primers 12
1.5. Chemical and Other Materials 14
2. Methods 22
2.1. Isolation of PMNs 22
2.2. Cell Culture 22
2.3. Bacterial Strains and Growth Conditions 22
2.4. Construction of Isogenic lukAB Deletion Mutant and Complemented Strains 23
2.4.1. Construction of Isogenic lukAB Deletion Mutant Strains 23
2.4.1.1. Plasmid DNA Isolation 23
2.4.1.2. Vector Preparation 24
2.4.1.3. Genomic DNA Isolation 24
2.4.1.4. Insert Preparation 24
2.4.1.5. Construction of lukAB Deleted Plasmid 25
2.4.1.6. Competent Cell Preparation 25
2.4.1.7. Transformation 26
2.4.1.8. Deletion of lukAB Gene 27
2.4.2. Construction of Complemented Strains 28
2.4.2.1. Plasmid Isolation 28
2.4.2.2. Construction of lukAB Complementation Plasmid 28
2.4.2.3. Competent lukAB Deleted Isogenic Mutant Cells Preparation 29
2.4.2.4. Transformation 29
2.5. PMNs Infection by S. aureus 29
2.6. Cytotoxicity Assay 30
2.7. NETs Formation and Extrusion Assay 30
2.8. LukAB Localization Assay 31
2.9. Trichloroacetic acid (TCA) Precipitation Assay 32
2.10. Cell Lysate Extraction Assay 32
2.11. Western Blot Analysis 33
2.12. Enzyme-Linked Immunosorbent Assay (ELISA) 34
2.13. Statistical Analysis 34
Chapter 3. Results 36
1. Generation of S. aureus lukAB-Positive and lukAB-Negative Isogenic Strains 36
2. Leukocidin AB is not the Sole Contributor to the NLRP3 Inflammasome Activation during S. aureus Infection 37
3. Leukocidin AB Induces Caspase-1-Mediated IL-1β Release and Necrotic Cell Death in PMNs 38
3.1. Leukocidin AB-Expressing S. aureus Promotes IL-1β Release and Cell Death in PMNs 38
3.2. Leukocidin AB-Promoted IL-1β Release from PMNs Is Dependent on Caspase-1 Activation 39
3.3. Leukocidin AB-Induced IL-1β Release in PMNs is Independent of the Pore-Forming Activity of GSDMD 40
3.4. Leukocidin AB-Induced Cell Death is Distinct from Pyroptosis 40
3.5. Leukocidin AB-Contributed Cell Death Shares the Features with Necrosis 41
3.6. Leukocidin AB Exhibits Potential Pore-Forming Activity on PMNs 42
4. Caspase-1/GSDMD Induces NETs Formation and Leukocidin AB Promotes NETs Extrusion 43
4.1. Caspase-1/GSDMD, but not Leukocidin AB, Contributes to the Formation of NETs in PMNs Infected with S. aureus 43
4.2. Leukocidin AB Promoted NETs Extrusion 45
Chapter 4. Conclusion 47
Chapter 5. Discussion 48
1. Roles of Pore-Forming Toxins in Promoting the Release of Processed-Immune Contents 48
2. Roles of Leukocidin AB in Inflammasome Activation in PMNs and Macrophages during S. aureus Infection 50
3. Resistance of PMNs to Caspase-1/GSDMD-Promoted Pyroptosis during Early S. aureus Infection 52
4. Virulence Factors Promoting Nets Formation during S. aureus Infections 54
5. Mechanisms Involving Leukocidin AB-Induced Necrosis via Extracellular or Intracellular Pathways 55
6. Potential Roles of Leukocidin AB in Exacerbating Inflammatory Diseases and Septicemia during S. aureus Infection 57
7. Targeting Leukocidin AB-Neutralizing Antibodies can be a Promising Therapeutic Approach 59
8. Limitations 60
8.1. Species-Specific Features of Leukocidin AB Leaves Limitation Approaching in Vivo Studies 60
8.2. Short Lifespan of PMN in Elucidating the Leukocidin AB-Triggered Immune Responses during the Longer Infection of S. aureus 60
References 61
Figures 80
Appendix 110
                                    

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