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研究生:陳斯婷
研究生(外文):Szu-Ting Chen
論文名稱:鑑定先天免疫受體於病毒引發疾病之角色
論文名稱(外文):Identification of innate immunity receptors in the pathogenesis of viral infection
指導教授:謝世良
指導教授(外文):Shie-Liang Hsieh
學位類別:博士
校院名稱:國立陽明大學
系所名稱:微生物及免疫學研究所
學門:生命科學學門
學類:微生物學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:英文
論文頁數:132
中文關鍵詞:先天免疫模式識別受體C-型凝集素登革病毒細胞激素風暴
外文關鍵詞:Innate immunityPattern recognitionC-type lectinDengue viruscytokine storm
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先天免疫系統是宿主抵禦外來致病原的第一道防線,其在致病原入侵所啟動之免疫機制扮演相當重要的角色。先天免疫系統主要靠吞噬細胞如中性球、巨噬細胞、樹突狀細胞來吞噬並溶解致病原。參與先天免疫反應的細胞表面有許多受體,包含Toll-like receptor (TLR)、C型凝集素 (C-type lectin)以及TREM (triggering receptor expressed on myeloid cells) 等等,這些受體又稱為模式識別受體 (pattern recognition receptors, PRRs),它們可以辨識致病原表面所特有的分子模組 (pathogen-associated molecular patterns, PAMPs)。日前研究顯示致病原的醣化構造可以作為PAMPs,然而先天免疫受體如何辨識整個病毒顆粒,病毒透過受體如何驅動免疫反應的機制尚不清楚。我們對於鑑別能夠與整個病毒顆粒作用的先天免疫受體感到興趣,並且想了解這些先天免疫受體於病毒感染引發疾病之角色。因此利用基因重組技術,選殖一系列表現在先天免疫細胞表面的受體蛋白,利用此蛋白陣列,篩選可與病毒顆粒結合的標的受體。
在這22個模式識別受體中,C-型凝集素包含DC-SIGN、DC-SIGNR及CLEC5A能夠與登革病毒顆粒結合。其中CLEC5A (又名MDL-1) 為C-型凝集素的成員,具有C-型凝集素特有的區塊並且與DAP12分子連結。CLEC5A與登革病毒結合後能活化DAP12分子。CLEC5A與登革病毒結合雖不影響病毒進入細胞的能力,但可刺激細胞產生前驅發炎細胞激素。透過擷抗性抗體以及干擾性RNA阻斷CLEC5A與登革病毒的結合,能有效抑制前驅細胞激素的產生卻不影響干擾素分泌,由此可知CLEC5A負責前驅發炎細胞激素的訊息傳導。此外,CLEC5A也參與登革抗體與登革病毒形成之免疫複合物 (immunocomplex)造成的抗體依賴性增強效應 (antibody dependent enhancement) 所釋放的前驅發炎細胞激素。
登革病毒感染會造成嚴重的登革出血熱及登革休克,其主要原因來自於血管通特性增加而導致的血漿滲漏以及血小板過低。我們的研究顯示,CLEC5A的擷抗性單株抗體不但能阻斷CLEC5A與登革病毒的結合,並可抑制登革病毒在STAT1缺損小鼠模式引起的血漿滲漏及皮下、腸胃道嚴重出血現象,及有效降低死亡率達50%。由於登革出血及登革休克至今尚無有效的治療方式,藉由CLEC5A擷抗性單株抗體阻斷CLEC5A的訊息傳導,可减少前趨細胞發炎激素釋放卻又不影響細胞抗病毒的能力。以CLEC5A做為治療登革出血熱標的乃是全新的觀念,此抗體可進一步發展成為藥物,以減輕病人組織受損的現象,並增加其存活率。
除了登革病毒,CLEC5A也會與其他同屬黃質病毒的日本腦炎病毒及西尼羅河病毒結合。此舉顯示CLEC5A可作為一模式識別受體, 辨識黃質病毒;透過阻斷黃質病毒與CLEC5A作用可以減緩病毒造成的發炎反應,對於黃質病毒造成的發炎疾病也有治療的潛力。除了登革病毒,CLEC5A也會與其他同屬黃質病毒的日本腦炎病毒及西尼羅河病毒結合。此舉顯示CLEC5A可作為一模式識別受體, 辨識黃質病毒;透過阻斷黃質病毒與CLEC5A作用可以減緩病毒造成的發炎反應,對於黃質病毒造成的發炎疾病也有治療的潛力。由於絕大多數的先天免疫受體其配體尚不清楚,因此被歸類為orphan receptor。先天免疫受體蛋白陣列不僅可以幫助我們鑑定岀與致病原的受體,更能幫助解開致病原與宿主細胞之間的反應機制,以進一步探究是否可作為治療的標的。
Innate immunity, the front line of host defense, is essential for the initiation of immune response upon pathogen invasion. The major effectors involved in innate immunity are neutrophils, macrophages, dendritic cells (DCs) and natural killer (NK) cells. Members of innate immunity receptors (including Toll-like receptors, C-type lectin receptors, TREM (triggering receptor expressed on myeloid cells)) are the principal ‘pattern recognition receptors’ (PRRs) on immune cells to recognize pathogen-associated molecular patterns (PAMPs). Recent studies indicate pathogen glycans can serve as PAMPs, but whether innate immunity receptors can recognize envelope glycans on the intact viral particle, and how viral particles trigger immune response via these PRRs are still unknown. Therefore, we are interested to identify the viron-interacting innate immunity receptors to understand their role in the pathogenesis of viral infection. To address these questions, twenty-two of PRRs expressed on innate immune cells were cloned by recombinant DNA technique, while the recombinant proteins were expressed by mammalian expression system for further screening.
Among the twenty-two of PRRs tested, DC-SIGN, DC-SIGNR, and CLEC5A were found to interact with dengue virus (DV) directly. CLEC5A (C-type lectin domain family 5, member A; also known as myeloid DAP12-associating lectin (MDL-1)) contains a C-type lectin-like fold similar to the natural-killer T-cell C-type lectin domains, and associates with a 12-kDa DNAX-activating protein (DAP12) on myeloid cells. We show that CLEC5A interacts with DV directly to induce DAP12 phosphorylation. Even though the CLEC5A–DV interaction does not result in viral entry, it stimulates the release of proinflammatory cytokines.
Dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS), the most severe responses of DV infection, are characterized by plasma leakage (due to increased vascular permeability) and low platelet counts. Blockade of CLEC5A–DV interaction suppresses the secretion of proinflammatory cytokines without affecting the release of IFN-α, supporting the notion that CLEC5A acts as a signaling receptor for proinflammatory cytokine release. Moreover, antagonistic anti-CLEC5A monoclonal antibodies inhibit DV-induced plasma leakage, subcutaneous and vital-organ haemorrhaging, and reduce the mortality of DV infection by about 50% in STAT1-deficient mice. Hence, our observation that blockade of CLEC5A-mediated signaling attenuates the production of proinflammatory cytokines by macrophages infected with DV (either alone or complexed with an enhancing antibody) offers a promising strategy for alleviating tissue damage and increasing the survival of patients suffering from DHF and DSS.
In addition to DV, Japanese encephalitis virus (JEV) and West Nile virus (WNV), other members in Flaviviridae family, interact with CLEC5A directly. This implies that CLEC5A might act as pattern recognition receptor. Since blockade of CLEC5A-JEV and CLEC5A-WNV interaction also suppresses the secretion of proinflammatory cytokines, this suggests that blockade of CLEC5A-DV interaction may apply to treat other flavivirus-induced inflammatory diseases. So far, the ligands of most of innate immune receptors are un-identified yet, thus are regarded as orphan receptors. The innate immune receptor-protein array will not only help to identify the pathogen-interacting receptors to further investigate their roles in host-pathogen interaction, but are also invaluable to understand whether they could become the potential therapeutic targets of human diseases in the future.
TABLE OF CONTENTS
中文摘要
ABSTRACT
INTRODUCTION
1. Innate immunity
1.1 Innate immune recognition
1.2 Toll-like receptors
1.3 TLRs signaling pathway in general
1.4 Non-toll-like intracellular innate immunity receptors and sensors
1.5 Triggering receptors expressed by myeloid cells (TREMs) family
2. Myeloid c-type lectins in innate immunity
2.1 C-type lectin superfamily
2.2 Myeloid C-type lectin in recognition of non-self antigen
2.3 Signaling cascade of myeloid C-type lectin receptors
2.4 Dual functions of myeloid C-type lectin receptors
3. Dengue virus
3.1 Structure and Life Cycle of DV
3.2 Dengue disease
3.3 Pathogenesis of DV Infection
OBJECTIVES
MATERIALS
1. Reagents, buffers and solutions
2. Culture media
3. Cells
4. Viruses
5. Mouse strains
METHODS
1. Bacterial culture
2. Preparation of DNA
3. Cloning techniques
4. Bacterial transformation
5. Reversed transcription-polymerase chain reaction (RT-PCR)
6. Small hairpin RNA (shRNA) preparation
7. Recombinant protein expression by 293 freestyle™ system
8. Immunopreicipitation
9. Western blotting
10. Virus infection and titration
11. Preparation and screening of monoclonal antibody
12. Cell culture
13. Flow cytometry analysis
14. Binding assay of viruses v.s. receptors
15. In vitro permeability assay
16. Mouse model
RESULTS
1. Interaction of DV with C-type lectin receptors
1.1 Establishment of innate immune receptors protein array
1.2 Interaction of DV with CLEC5A
1.3 The participation of glycans in CLEC5A-DV interaction
2. Expression pattern of CLEC5A in immune cells
3. CLEC5A is essential for DV-induced DAP12 phosphorylation, but not for DV entry
3.1 Induction of DV-mediated DAP12 phosphorylation via CLEC5A
3.2 CLEC5A does not mediate DV entry into humann MDMs
4. TNF-α secretion from human MDMs through DV replication-dependent manner and –independent manner
5. 5. CLEC5A is critical for DV-mediated secretion of proinflammatory cytokines, but not IFN-α
6. Synergistic effect of CLEC5A and TLR7 in DV infection
7. Generation of antagonistic anti-CLEC5A mAbs7. Generation of antagonistic anti-CLEC5A mAbs to attenuate DV-mediated inflammatory reactions
8. Antagonistic anti-CLEC5A mAbs abolish inflammatory cytokine secretion by DV serotype 1-4
9. CLEC5A is critical for ADE-mediated secretion of TNF-α
10. CLEC5A antagonistic mAbs rescue permeability change of endothelia cells
11. Murine CLEC5A is also involved in DV-induced inflammation
12. Establishment of DV-challenged model in mouse
13. Antagonisitc anti-CLEC5A mAbs rescue mice from DV-induced plasma leakage
14. Administration of anti-CLEC5A mAb reduces serum level of DV-induced cytokine and chemokine
DISCUSSION
REFERENCE
FIGURES
TABLES
APPENDIX
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