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研究生： 齊嘉鈺
Chi, Chia-Yu
論文名稱： 社區性抗甲氧苯青黴素金黃色葡萄球菌在皮膚及軟組織感染的致病機轉: Panton-Valentine Leukocidin的角色
Pathogenesis of Community-Associated Methicillin-Resistant Staphylococcus aureus in Skin and Soft Tissue Infection: The Role of Panton-Valentine Leukocidin
指導教授： 劉清泉
Liu, Ching-Chuan
林秋烽
Lin, Chiou-Feng
學位類別： 博士
Doctor
系所名稱： 醫學院 - 臨床醫學研究所
Institute of Clinical Medicine
論文出版年： 2014
畢業學年度： 102
語文別： 英文
論文頁數： 102
中文關鍵詞： 核內體 、角質細胞 、Panton-Valentine 殺白細胞素 、金黃色葡萄球菌
外文關鍵詞： endosome, keratinocyte, Panton-Valentine leukocidin, Staphylococcus aureus
相關次數： 點閱：148  下載：1 
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    • 金黃色葡萄球菌是造成人類感染的重要原因，而且其所引起的臨床症狀嚴重度差異非常大。另一方面，由於抗藥性的問題日益嚴重，社區性抗甲氧苯青黴素金黃色葡萄球菌造成的皮膚及軟組織感染，在最近十年內，已然成為全世界一個相當重要且棘手的問題。社區性抗甲氧苯青黴素金黃色葡萄球菌造成感染及流行原因極有可能與其所表現的毒性因子有關。根據流行病學的報告顯示，會引起皮膚及軟組織感染的社區性抗甲氧苯青黴素金黃色葡萄球菌菌株幾乎都會表現一種特有的毒性因子，稱為Panton-Valentine 殺白細胞素 (Panton-Valentine leukocidin，PVL)。但是過去的研究報告大多僅侷限於流行病學的觀察，而關於PVL在社區性抗甲氧苯青黴素金黃色葡萄球菌所引起皮膚及軟組織感染中的重要性，我們所知道的卻是非常有限。本論文中，我利用台灣最常見造成皮膚及軟組織感染，同時會表現PVL的社區性抗甲氧苯青黴素金黃色葡萄球菌，和根據該菌株，利用基因重建方式，所構築的PVL剔除突變株以及PVL再表現的衍生株，探討PVL在社區性抗甲氧苯青黴素金黃色葡萄球菌感染人類角質細胞以及兔子的動物實驗中，致病機制上的重要角色。結果發現，無論是帶有PVL的社區性抗甲氧苯青黴素金黃色葡萄球菌野生株，或是PVL剔除突變株，都會在感染角質細胞1小時內附著在宿主細胞表面，隨後被吞入核內體 (endosome)內。然而，在感染2小時後，相較於PVL剔除突變株，表現PVL的社區性抗甲氧苯青黴素金黃色葡萄球菌會明顯有效地破壞核內體，逃脫進入細胞質中，並且開始在胞內進行複製。此外，與感染PVL剔除突變株的細胞相比，此時感染帶有PVL的社區性抗甲氧苯青黴素金黃色葡萄球菌的角質細胞會被觸發而大量製造活性含氧物種 (reactive oxygen species, ROS)。感染6小時後，帶有PVL的社區性抗甲氧苯青黴素金黃色葡萄球菌會導致更多與caspase活化路徑相關的角質細胞凋亡發生。進一步，在兔子的感染模式中也可以觀察到，在感染皮內一週後，帶有PVL的社區性抗甲氧苯青黴素金黃色葡萄球菌，會比PVL剔除突變株造成更大範圍的皮膚及軟組織損傷，以及細胞凋亡發生。並且，相較於PVL剔除突變株的感染部位，感染帶有PVL的社區性抗甲氧苯青黴素金黃色葡萄球菌的皮膚組織，會大量表現促發炎反應相關的細胞素、趨化素或是受體。這些結果證明，藉由協助菌株破壞宿主細胞核內體、提早進入細胞質中、於胞內大量複製、觸發ROS的產生、引發細胞凋亡，以及促使細胞大量表現促發炎相關的細胞素，PVL確實是社區性抗甲氧苯青黴素金黃色葡萄球菌導致壞死性皮膚感染的重要毒性因子。這些PVL對於社區性抗甲氧苯青黴素金黃色葡萄球菌在人類角質細胞和動物的感染模式中的重要性，證實PVL不僅僅是社區性抗甲氧苯青黴素金黃色葡萄球菌的一個標記，它更可能是未來控制感染部位不當的發炎反應和細胞死亡，一個相當有希望的治療標的。

    Staphylococcus aureus is a leading cause of human infections. The pathogen is able to cause a wide range of diseases of varied severity. Skin and soft tissue infections (SSTIs) caused by community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) have emerged as major health problems throughout the world. CA-MRSA infection has been attributed to several virulence factors. Epidemiological reports demonstrate that most SSTI CA-MRSA strains produce Panton-Valentine leukocidin (PVL), but its contribution to CA-MRSA pathogenesis is poorly defined. In this thesis I used an endemic PVL-positive SSTI-causing CA-MRSA strain from Taiwan, together with an isogenic PVL-knockout mutant (Δpvl) and complemented PVL-positive derivative to evaluate the role of PVL in the pathogenesis of CA-MRSA in the RHEK-1 human keratinocyte cell line and a rabbit skin infection model. I found that both PVL-positive CA-MRSA and isogenic Δpvl strains attached and were engulfed into endosomes of RHEK-1 cells within 1h following infection. However, by 2h post-infection PVL-positive CA-MRSA more effectively disrupted endosomes, escaped into the cytoplasm, and replicated intracellularly. Additionally, PVL-positive CA-MRSA induced higher reactive oxygen species (ROS) production than the isogenic Δpvl mutant strains after 2h of infection. By 6h post-infection the PVL-positive strain caused significantly more caspase-dependent keratinocyte apoptosis than the isogenic Δpvl mutant. In rabbit infection model, one week following infection the wild type strain produced significantly more widespread lesions and cell apoptosis than the isogenic Δpvl mutant. Moreover, the expressions of mRNA of proinflammatory cytokines, chemokines, and receptors at the skin lesions were significantly increased by infected with wild type PVL-positive CA-MRSA isolate than the isogenic Δpvl mutant. These findings indicate that PVL is an important virulence factor that enables CA-MRSA to produce necrotizing skin infections by allowing the bacteria to escape from endosomes, replicate intracellularly, trigger ROS production, induce apoptosis, and increase the expression of proinflammatory mediators. The significant contribution of PVL to CA-MRSA virulence in both human keratinocytes and animal infection models suggests that PVL is not only a marker of CA-MRSA, but also a potential therapeutic target to control the inappropriate inflammation and cell death at the infection sites.

    Chapter 1 Introduction 1 1-1 Community-Associated Methicillin-Resistant Staphylococcus aureus 1 1-2 CA-MRSA Virulence Factor — Panton-Valentine Leukocidin 4 1-3 Infection Model to Study PVL 5 1-4 Thesis Hypothesis and Aims 7 Chapter 2 Materials and Methods 9 2-1 Antibody 9 2-2 Bacterial Strains and Growth Conditions 9 2-3 Pulsed Field Gel Electrophoresis 10 2-4 Construction of Isogenic LukF/S-PV Deletion Mutant and Complemented Strains 12 2-5 Eukaryotic Cell Culture 13 2-6 Invasion Assay 13 2-7 Co-Immunoprecipitation 13 2-8 Determination of CFU 14 2-9 Measurement of Cell Death 15 2-10 Measurement of ROS 15 2-11 Confocal Fluorescence and Electron Microscopy 16 2-12 Rabbit Skin Infection Model 17 2-12-1 Skin and soft tissues infection 17 2-12-2 Histopathogical analysis 18 2-12-3 TUNEL assay 18 2-12-4 Gene expression of chemokines, cytokines and receptors 19 2-13 Statistical Analysis 20 Chapter 3 Results 21 3-1 Clinical Isolates 21 3-2 Morphological Characteristics of Human Necrotizing Fasciitis 21 3-3 PVL Is a Virulence Determinant in CA-MRSA Infected Human Keratinocytes 22 3-3-1 Generation of CA-MRSA PVL-positive and PVL-negative isogenic strains 22 3-3-2 PVL does not interfere with the ability of CA-MRSA to invade keratinocytes 23 3-3-3 PVL Enhances endosomal destruction and escape 23 3-3-4 PVL facilitates S. aureus intracellular replication 24 3-3-5 PVL triggers caspase-dependent cell death 24 3-3-6 PVL induces ROS generation 25 3-4 PVL Is an Important Virulence Determinant in a Rabbit SSTI Model 26 3-4-1 Macroscopic description of the development of lesions 26 3-4-2 Histological examination 26 3-4-3 Detection of apoptosis 27 3-4-4 Gene expression of chemokines, cytokines, and receptors 27 Chapter 4 Conclusions 29 Chapter 5 Discussion and Prospects 30 References 39 Table 56 Figures 58 Appendix 78 Curriculum Vitae 83

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