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系統識別號 U0026-1508202011000300
論文名稱(中文) 金屬鋅抑制達卡產氣單胞菌感染引起之NLRP3發炎小體活化
論文名稱(英文) Zinc inhibits NLRP3 inflammasome activation induced by Aeromonas dhakensis infection
校院名稱 成功大學
系所名稱(中) 微生物及免疫學研究所
系所名稱(英) Department of Microbiology & Immunology
學年度 108
學期 2
出版年 109
研究生(中文) 舒青瑩
研究生(英文) Cing-Ying Shu
學號 S46074093
學位類別 碩士
語文別 英文
論文頁數 46頁
口試委員 指導教授-陳柏齡
口試委員-陳昌熙
口試委員-陳振暐
口試委員-吳綺容
中文關鍵字 達卡產氣單胞菌  NLRP3發炎小體  金屬鋅 
英文關鍵字 Aeromonas dhakensis  NLRP3 inflammasome  zinc 
學科別分類
中文摘要 達卡產氣單胞菌 (Aeromonas dhakensis) 是一種會引起人類嚴重感染性疾病的病原菌,且在台灣南部尤其盛行。A. dhakensis已經被報導發現許多毒力因子,例如:由 ahh1 和 aerA 所編碼的穿孔素、由 ast 所編碼的內毒素、由 ascV 和 ascF-G 所編碼的III型分泌系統相關蛋白。但是目前尚未釐清A. dhakensis的分子性致病機制。NLRP3發炎小體是由NLRP3 (感應子)、ASC (銜接子)、胱天蛋白酶-1 (效應子) 所組裝而成的多蛋白複合物。活化的NLRP3發炎小體會促進促炎性細胞因子:白介素1β(IL-1β)和白介素18(IL-18)的成熟及分泌,並且導致名為細胞焦亡的細胞程序性死亡現象。我們的主要目的是探討A. dhakensis感染是否會造成NLRP3發炎小體活化和細胞死亡,並且開發具有潛力的治療策略以對抗A. dhakensis造成的嚴重感染。在這項研究中,我們發現A. dhakensis的感染會誘導細胞死亡,並且使巨噬細胞中的胱天蛋白酶-1活化以及白介素1β分泌。接下來,我們表明鋅可抑制NLRP3發炎小體的活化,並伴隨Nrf2下游基因,包括:NAD(P)H脫氫酶(NQO1)、血紅素加氧酶-1(HO-1)表現上調。總而言之,我們揭露鋅可以抑制 A. dhakensis 感染所造成的NLRP3發炎小體活化,並且具有作為A. dhakensis嚴重感染治療策略的潛力。
英文摘要 Aeromonas dhakensis is an important human pathogen that causes severe infectious diseases and syndromes in humans in south Taiwan. Many virulence genes, such as pore-forming toxins encoded by ahh1 and aerA, enterotoxins encoded by ast, T3SS-related proteins encoded by ascV, and ascF-G have been discovered in this species. However, the molecular pathogenicity in A. dhakensis remains unclear. The NOD-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasomes, consists of multiple proteins, including NLRP3, the adapter molecule apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and the effector molecule pro-caspase-1. The activated NLRP3 inflammasome promotes the maturation and secretion of inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18), and causes pyroptosis, which is a type of programmed cell death. Our specific aim is to investigate whether A. dhakensis infection induces NLRP3 inflammasome activation and cell death and to develop a potential therapeutic strategy for severe A. dhakensis infection. In this study, we observed that A. dhakensis infection induced cell death, as well as caspase-1 maturation and IL-1β secretion in macrophages. In contrast, a deficiency of NLRP3 reduced cell death, caspase-1 maturation, and IL-1β secretion in A. dhakensis infection. Next, we showed that zinc inhibited NLRP3 inflammasome activation accompanied with upregulation of the Nrf2 downstream gene, including NAD(P)H Quinone Dehydrogenase 1 (NQO1) and heme oxygenase-1 (HO-1). In summary, our data demonstrates that zinc-inhibited inflammasome activation is a potential therapeutic strategy for severe A. dhakensis infection.
論文目次 中文摘要 I
Abstract II
Acknowledgements IV
Contents VI
Introduction 1
Aeromonas 1
Aeromonas dhakensis 1
Inflammasome 4
NLRP3 Inflammaosme 6
Zinc 8
Nrf2 Pathway 9
Materials and methods 12
Bacteria strain 12
Cell line culture and treatment 12
Cytotoxicity assay 13
Western blotting 14
Growth counts 15
RNA extraction and Real-Time PCR 15
Results 17
A. dhakensis induced cytotoxicity to different cell lines. 17
A. dhakensis induced caspase-1 activation and IL-1β secretion from THP-1 rather than RAW 264.7. 17
A. dhakensis infection induced caspase-1 activation and IL-1β secretion through the NLRP3 inflammasome. 18
Zinc co-treatment reduced cell damage caused by A. dhakensis infection in THP-1 cell. 19
Zinc co-treatment reduced secretion of IL-1 β from THP-1 infected with A. dhakensis. 19
Zinc co-treatment induced Nrf2 downstream gene expression in THP-1 infected with A. dhakensis. 20
Conclusion 21
Discussion 22
References 26
Tables 40
Table 1. The qRT-PCR primers used in this study. 40
Figures 41
Figure 1. Cytotoxicity of THP-1, RAW 264.7, and C2C12 infected with A. dhakensis. 41
Figure 2. Detection of caspase-1 maturation and IL-1β released from THP-1 and RAW 264.7 induced by A. dhakensis infection via a western blot. 42
Figure 3. A. dhakensis-induced caspase-1 maturation, IL-1β secretion, and LDH release were reduced in THP-1 NLRP3-/- cells. 43
Figure 4. Zinc co-treatment significantly protected THP-1 from A. dhakensis infection. 44
Figure 5. Zinc co-treatment reduced caspase-1 maturation and IL-1β secretions from THP-1 induced by A. dhakensis. 45
Figure 6. A. dhakensis infection and Zinc co-treatment affected the expression of genes in the Nrf2 pathway in THP-1 46
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