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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 伍安怡 | |
dc.contributor.author | Tzu-Hsuan Chang | en |
dc.contributor.author | 張子軒 | zh_TW |
dc.date.accessioned | 2021-06-16T10:27:04Z | - |
dc.date.available | 2018-09-24 | |
dc.date.copyright | 2013-09-24 | |
dc.date.issued | 2013 | |
dc.date.submitted | 2013-08-15 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/60712 | - |
dc.description.abstract | 先天免疫系統(innate immunity system)是對抗外來病原菌感染時的第一道防線。在我的研究中探討樹突細胞 (BMDCs) 以及巨噬細胞 (BMDMs & thio-pMac) 在感染組織包漿菌時引發炎性體的活化機制。
組織胞漿菌是一種雙型態的真菌,自然狀況下以菌絲的型態生長於土壤中,一旦吸入動物體內,會寄生在巨噬細胞 (macrophages) 吞噬小體內進行繁衍。除此之外,研究發現酵母型組織胞漿菌可以被樹突細胞 (dendritic cells) 所吞噬並且呈現抗原給T細胞。因此,在先天免疫系統中,巨噬細胞和樹突細胞扮演著抵禦組織包漿菌感染的重要角色。 炎性體 (inflammasome) 是一多蛋白組合而成的胞內感應平台。有別於胞外的細胞受體,炎性體做為細胞質內感應外來物 (PAMPs) 的胞內受體 (PRRs)。在我的研究裡,探討組織胞漿菌感染樹突細胞以及巨噬細胞後是否會引起的炎性體的活化。在細胞吞噬組織胞漿菌之後,會傳遞訊號生成pro-IL-1β,以及活化細胞內的 caspase-1,進而導致活化的caspase-1 去切pro-IL-1β使之成為成熟型的IL-1β而分泌出細胞外。在使用NLRP3 的基因剔除鼠的樹突細胞感染組織胞漿菌的實驗結果顯示少了NLRP3的細胞,在感染組織胞漿菌後便無法產生成熟型的IL-1β同時也沒有caspase-1的活化,顯示NLRP3 在胞內會辨識組織胞漿菌並且引發炎性體的組成與活化。而用抗體抑制住樹突細胞外的細胞受體,再感染組織胞漿菌後,可以發現Dectin-2 扮演著辨識組織胞漿菌並且傳遞訊息活化炎性體的角色。從我的實驗結果顯示,Dectin-2會誘導MAPK活化傳遞下游訊息去引起訊息一:Il-1β mRNA 的轉錄導致pro-IL-1β的生成,以及訊息二:caspase-1的活化。 因此在組織胞漿菌感染引起的炎性體活化中,Dectin-2會辨識組織胞漿菌並且傳遞訊息一以及訊息二去活化炎性體。 | zh_TW |
dc.description.abstract | The innate immune system is the first line to defend the invasion of microbes. In this study, I investigated inflammation activation in bone marrow-derived dendritic cells (BMDCs), macrophages (BMDMs) and thioglycollate-elicited peritoneal macrophages (thio-pMacs) after infection by Histoplasma capsulatum.
Histoplasma capsulatum is an opportunistic dimorphic fungal pathogen. It grows in the soil in nature as mycelium form and transforms into yeast after the microconidia enter into the lungs through inhalation. The yeast form of Histoplasma is an intracellular pathogen of the macrophage. Dendritic cells take up Histoplasma and present fungal antigens to both CD4 and CD8 T cells. Therefore, the roles of macrophages and dendritic cells and their interactions with the fungus are important to defense against Histoplasma infection. Inflammasome is an intracellular protein sensor platform that composes of multiple protein complexes. Unlike membrane bound Toll-like receptors (TLRs), Nod-like receptors (NLRs) serve as cytosolic pattern recognition receptors to recognize PAMPs in the host. Here, I investigated the mechanism of inflammasome activation in the BMDCs, BMDMs and thio-pMacs after stimulation with Histoplasma. Both BMDCs and thio-pMacs stimulated with Histoplasma triggered caspase-1 activation and production of interleukin-1β (IL-1β). I used NLRP3 knockout mice to investigate whether Histoplasma engages NLRP3 in BMDCs. Cells with NLRP3-deficiency failed to produce IL-1β after Histoplasma infection. These results demonstrated that NLRP3 is the major PRR in the cytosol to recognize Histoplasma and mediates inflammasome activation. Using blocking antibodies I demonstrated that Dectin-2 played an important role in the induction of IL-β production and Caspase-1 activation after Histoplasam infection in BMDCs. Dectin-2 induced downstream MAPK activation to trigger both the first signal (the transcription of Il-1β) and the second signal (activation of caspase-1) in BMDCs. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T10:27:04Z (GMT). No. of bitstreams: 1 ntu-102-R00449013-1.pdf: 56194915 bytes, checksum: 931b288b068f27dedc48a94f6a8c5dc0 (MD5) Previous issue date: 2013 | en |
dc.description.tableofcontents | Content
致謝 ..................................................... i English Abstract ................................................................................................. ii Chinese Abstract ................................................................................................. iv Abbreviations ...................................................................................................... vi Contents .................................................................................................... vii List of figures ....................................................................................................... xii Chapter I. Introduction ...................................................................................... 1 1. Histoplasma capsulatum ........................................................................... 1 1.1 Histoplasma capsulatum infection ....................................................... 1 1.2 Host defense against Histoplasma capsulatum .................................... 2 1.3 The interaction between host cell specific receptors and Histoplasma 2 2. Pattern recognition receptors .................................................................... 3 2.1 The TLRs family .................................................................................. 3 2.2 The CLRs family .................................................................................. 4 2.3 The NLRs family ................................................................................. 4 2.4 Inflammasomes .................................................................................... 5 2.5 The NLRP3 inflammasome ................................................................. 5 2.6 Activation of inflammasome ................................................................ 6 3. Pathogens that induce inflammasome activation ................................... 7 3.1 Candida albicans ................................................................................. 7 3.2 Aspergillus fumigatus ........................................................................... 7 3.3 Mycobacterium tuberculosis ................................................................ 8 3.4 Shistosoma mansoni ............................................................................. 8 Chapter II. Aims of the study ............................................................................. 10 Specific Aims ...................................................................................................... 10 Chapter III Materials and Methods .................................................................. 13 Part I. Materials .................................................................................................. 13 1. Mice .......................................................................................................... 13 2. Antibodies ................................................................................................. 13 3. Inhibitors ................................................................................................... 16 4. RT-qPCR primer sequence ....................................................................... 16 5. Solutions ................................................................................................... 18 6. Chemicals and reagents ............................................................................. 21 7. Disposable ................................................................................................. 22 8. Equipments ................................................................................................ 23 Part II. Methods .................................................................................................. 24 1. Cells .......................................................................................................... 24 1.1 Bone marrow derived-dendritic cells (BMDCs) ................................. 24 1.2 Bone marrow derived-macrophages (BMDMs) ................................. 25 1.3 Thioglycollate-elicitated peritoneal macrophages (thio-pMacs) ........ 25 2. Fungus ....................................................................................................... 25 3. Staining of cell surface markers and receptors ......................................... 26 4. IL-1β, TNF and IL-6 ELISA assays .......................................................... 26 5. Western blotting ........................................................................................ 27 6. LDH assay ................................................................................................. 27 7. Real-time PCR .......................................................................................... 28 8. Statistics .................................................................................................... 29 Chapter IV. Results ............................................................................................. 30 1. Histoplasma yeast cells induce caspase-1-dependent inflammasome activation in BMDCs ................................................................................ 30 2. Histoplasma yeast cells induce inflammasome activation in thio-pMacs but not in BMDMs .................................................................................... 32 3. Blocking Dectin-2 reduces caspase-1 p20 and IL-1β p17 production in BMDCs after Histoplasma stimulation .................................................... 32 4. Blocking Dectin-2 in WT BMDCs reduces Il-1β gene expression .......... 34 5. Blocking Dectin-2 in Dectin-1-deficient BMDCs completely inhibits caspase-1 p20 and IL-1β p17 production ................................................. 35 6. Histoplasma induces MAPK signaling in BMDCs in a Dectin-2-dependent manner .................................................................................... 36 7. JNK, ERK and p38 control inflammasome activation ............................. 37 8. Histoplasma-induced inflammasome activation is NLRP3-dependent .... 38 9. Potassium efflux and cathepsin B function as signal 2 in Histoplasma-induced inflammasome activation ............................................................ 39 Chapter V. Discussion ........................................................................................ 41 1. Live Histoplasma induces stronger second signal than heat-killed yeast ......................................................................................................... 41 2. Histoplasma-induced caspase-1-dependent inflammasome activation in BMDCs .................................................................................................... 43 3. Different populations of macrophages response differently to Histoplasma .............................................................................................. 43 4. Dectin-2 mediates both the first and second signals for inflammasome activation in BMDCs response to Histoplasma stimulation ..................... 44 5. Both Dectin-2 and Dectin-1 play a role in inflammatory response to Histoplasma ............................................................................................. 45 6. ERK, JNK and p38 downstream of Dectin-2 control inflammasome activation ................................................................................................... 46 7. MAPK signaling molecules play distinct roles in inflammasome activation and cytokine production ........................................................... 48 8. Histoplasma induces NLRP3-dependent inflammaseom activation ......... 49 9. Cathepsin B and potassium efflux are the second signals that activate Histoplasma-induced NLRP3 inflammasome ......................................... 50 10. Conclusions ............................................................................................... 51 Chapter VI. References ....................................................................................... 53 Chapter VII. Figures ........................................................................................... 60 | |
dc.language.iso | en | |
dc.title | 探討細胞受體以及訊息傳遞在組織胞漿菌感染下引發炎性體活化 | zh_TW |
dc.title | To identify receptor(s) and signals that are involved in inflammasome activation by Histoplasma capsulatum | en |
dc.type | Thesis | |
dc.date.schoolyear | 101-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 李建國,朱清良,徐立中 | |
dc.subject.keyword | 組織胞漿菌,炎性體, | zh_TW |
dc.subject.keyword | Histoplasma,inflammasome, | en |
dc.relation.page | 95 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2013-08-15 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 免疫學研究所 | zh_TW |
顯示於系所單位: | 免疫學研究所 |
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