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系統識別號 U0026-3007201315471600
論文名稱(中文) 以小鼠模式探討肥大細胞在登革病毒感染中扮演 的角色
論文名稱(英文) Role of mast cells in mouse models of dengue virus 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 101
學期 2
出版年 102
研究生(中文) 朱雅婷
研究生(英文) Ya-Ting Chu
學號 S46004111
學位類別 碩士
語文別 英文
論文頁數 77頁
口試委員 指導教授-林以行
口試委員-郭志峰
口試委員-劉清泉
口試委員-林秋烽
口試委員-羅伯安德森
中文關鍵字 登革病毒  肥大細胞  脫粒作用  KitW-sh/W-sh小鼠 
英文關鍵字 dengue virus  mast cell  degranulation  KitW-sh/W-sh mice 
學科別分類
中文摘要 登革病毒 (dengue virus; DENV)屬於黃熱病毒科、黃熱病毒屬的其中一員,根據血清型的不同可區分成四種血清型。受登革病毒感染的病人可能會有較輕微的登革熱 (dengue fever; DF)以及較嚴重的登革出血熱 (dengue hemorrhagic fever; DHF)或登革休克症(dengue shock syndrome; DSS)等症狀出現。肥大細胞 (mast cell)被推測可能參與在登革病毒感染中是由於過去報導指出,登革出血熱病人尿液中組織胺 (histamine)增多,組織胺是肥大細胞最主要的顆粒因子。然而,肥大細胞在登革病毒感染中扮演的角色尚未釐清,過去研究報導指出受登革病毒感染的肥大細胞株會產生腫瘤壞死因子 (TNF-α)、介白素-1 (IL-1β)和介白素-6 (IL-6)以及趨化激素MIP-1α, MIP-1β和RANTES,這些因子可能作用於血管以及吸引白血球 (leukocyte)至感染部位。肥大細胞也可在登革病毒感染中吸引自然殺手細胞 (NK cell)和自然殺手T細胞 (NKT cell)來清除病毒。我們利用較容易受登革病毒感染的STAT1-/-小鼠模式來探討肥大細胞在其中扮演的角色。實驗結果顯示,受登革病毒感染的小鼠其感染部位的肥大細胞會有明顯的脫粒作用 (degranulation),並且此現象必須由活病毒進行複製所誘導。然而我們發現進行脫粒作用的肥大細胞並沒有被登革病毒感染。除此之外,過去實驗室研究顯示,給予受登革病毒感染小鼠抗ΔC NS1以及抗DJ NS1抗體可以提供保護效果,在此研究中,我們也發現給予抗ΔC NS1以及抗DJ NS1抗體可以有效的降低肥大細胞脫粒作用以及趨化激素RANTES 和MCP-1的表現,進一步也可以降低巨噬細胞 (macrophage)的浸潤。我們推測登革病毒可能先感染內皮細胞或巨噬細胞而產生趨化激素,這些趨化激素再刺激肥大細胞進行脫粒作用分泌調節因子。巨噬細胞與肥大細胞之間的互相活化可能會導致更多的細胞激素或趨化激素產生而造成內皮細胞活化或損傷。我們進一步使用肥大細胞缺失的KitW-sh/W-sh小鼠探討肥大細胞在登革病毒感染中扮演的角色。實驗結果顯示,登革病毒感染使得KitW-sh/W-sh小鼠出血時間較WT小鼠長。KitW-sh/W-sh小鼠也被觀察到有較多的登革病毒抗原NS3表現。除此之外,在感染部位我們觀察到KitW-sh/W-sh小鼠在未感染病毒的狀態下,趨化激素(MCP-1, RANTES, IP-10)的表現量就比WT小鼠高;而登革病毒感染後使得這些趨化激素表現更多。然而除了IP-10,其他在血清中的趨化激素則沒有統計上的明顯差異。未受登革病毒感染KitW-sh/W-sh小鼠的巨噬細胞數量也較WT小鼠多,感染之後可以誘導更多的巨噬細胞浸潤。由這些結果得知KitW-sh/W-sh小鼠較易受登革病毒感染並造成發炎與血管的反應。
英文摘要 Dengue virus (DENV) is a member of the family Flaviviridae and consists of four serotypes DENV-1, -2, -3 and -4. DENV infection causes dengue fever (DF), dengue hemorrhagic fever (DHF), or dengue shock syndrome (DSS). It has been speculated that mast cells may play a role in DENV disease. For example, DHF patients exhibit increased level of urinary histamine which is a major granule-associated mediator from mast cells. However, the precise involvement of mast cells in DENV infection is unclear. Previous studies reported that DENV-infected human mast cells induce production of cytokines (TNF-α, IL-6, IL-1β) and chemokines (MIP-1α, MIP-1β, RANTES). These findings suggest that mast cells may play a role in vascular perturbation as well as leukocyte recruitment. Another study showed that DENV-infected mast cells recruit NK and NKT cells to the infection site to clear virus. In this study, we used mouse models to clarify the roles of mast cells in DENV infection. We have established a DENV-induced hemorrhage model in STAT1-/- mice which are susceptible to DENV. Our data showed that DENV but not UV-inactivated DENV enhanced mast cell degranulation in STAT1-/- mice. However, the degranulated mast cells were not infected by DENV. In addition, our previous study showed that anti-ΔC NS1 and anti-DJ NS1 antibodies (Abs) provided protection in DENV-infected STAT1-/- mice. In this study, we also found that treatment with anti-ΔC NS1 and anti-DJ NS1 Abs resulted in a reduction of mast cell degranulation and RANTES and MCP-1 production as well as macrophage infiltration. We hypothesize that DENV-infected endothelial cells or macrophages produce chemokines and further induce mast cell activation. Interactions between macrophages and mast cells may result in more cytokine production and cause endothelial cell damage or activation. We further investigated the roles of mast cells in mast cell-deficient KitW-sh/W-sh mice. The results showed a more prolonged bleeding time in DENV-infected KitW-sh/W-sh mice than in wild-type (WT) mice. More NS3 antigen was detected at the local infection site in DENV-infected KitW-sh/W-sh mice than in DENV-infected WT mice. The basal levels of MCP-1, IP-10, and RANTES at the local infection site were higher in KitW-sh/W-sh mice than in WT mice. After DENV infection, the expression of MCP-1, IP-10, and RANTES at the local infection site were significantly increased in KitW-sh/W-sh mice, but there were no significant differences in serum levels, except for IP-10. The basal numbers of infiltrating macrophages were also higher in KitW-sh/W-sh mice than in WT mice. After DENV infection, the numbers of infiltrating macrophages were significantly increased in KitW-sh/W-sh mice. In summary, compared to WT mice, KitW-sh/W-sh mice show enhanced sensitivity to DENV and resultant inflammatory and vascular responses.
論文目次 中文摘要 I
Abstract III
Acknowledgement V
Contents VI
Figure List IX
Abbreviations XI
Introduction 1
Characteristics of dengue virus 1
Epidemiology of dengue virus 3
Clinical symptoms of dengue virus infection 4
The pathogenesis of dengue virus infection 5
Host target cells for dengue virus 10
Animal models of dengue virus infection 11
Characteristics of mast cells 12
Characteristics of KitW-sh/W-sh mice 14
Specific Aims 16
1. To investigate the responses of mast cells to DENV-infection in mice. 16
2. To investigate the effects of anti-ΔC NS1 and anti-DJ NS1 Abs on mast cells in DENV-infected STAT1-/- mice. 16
3. To investigate the role of mast cells in DENV infection using the mast cell-deficient KitW-sh/W-sh mice. 16
Materials and Methods 18
A. Materials 18
A-1 Mice 18
A-2 Cell lines 18
A-3 Virus 18
A-4 Preparation of recombinant proteins and Abs 19
A-5 Drugs and reagents 19
A-6 Antibodies 22
A-7 Kits 23
A-8 Consumables 23
A-9 Instruments 24
B. Methods 26
B-1 Cell cultures 26
B-2 Virus culture 26
B-3 Plaque assay 26
B-4 Therapeutic model 26
B-5 Infection model 27
B-6 Bleeding time 27
B-7 Mast cell staining 27
B-8 Detection of serum cytokine levels 27
B-9 Detection of serum chemokine levels 28
B-10 Immunohistochemistry staining 29
B-11 Statistics 30
Results 31
1. To investigate the responses of mast cells to DENV-infection in mice. 31
1.1 A DENV infection model in STAT1-/- mice. 31
1.2 Mast cell degranulation in response to DENV. 31
1.3 Degranulated mast cells are not infected by DENV. 33
2. To investigate the effects of anti-ΔC NS1 and anti-DJ NS1 Abs on mast cells in DENV-infected STAT1-/- mice. 33
2.1 A therapeutic model in STAT1-/- mice. 33
2.2 Anti-ΔC NS1 and anti-DJ NS1 Abs reduce DENV-induced mast cell degranulation in STAT1-/- mice. 33
2.3 Anti-ΔC NS1 and anti-DJ NS1 Abs reduce DENV-induced chemokine production and macrophage infiltration in STAT1-/- mice. 34
3. To investigate the role of mast cells in DENV infection using the mast cell-deficient KitW-sh/W-sh mice. 35
3.1 A DENV infection model in WT and KitW-sh/W-sh mice. 35
3.2 Bleeding times of DENV-infected WT and KitW-sh/W-sh mice. 36
3.3 DENV antigen expression at local infection site in WT and KitW-sh/W-sh mice. 36
3.4 Production of chemokines and macrophage infiltration in WT and KitW-sh/W-sh mice. 37
3.5 Low viral dose-infected mice on 3 d.p.i. show a similar pattern of bleeding time and macrophage infiltration as high viral dose-infected mice on 2 d.p.i. 37
Discussion 39
References 45
Figures 57
Curriculum Vitae 77
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