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研究生：	李政勳 Li, Zheng-Syun
論文名稱：	人類腸病毒A71型感染纖溶酶原基因剔除小鼠的病理表現 Biological Characteristics of Human Enterovirus A71 in Plasminogen Knockout Mice
指導教授：	張權發 Chang, Chuan-Fa
學位類別：	碩士 Master
系所名稱：	醫學院 - 醫學檢驗生物技術學系 Department of Medical Laboratory Science and Biotechnology
論文出版年：	2019
畢業學年度：	107
語文別：	英文
論文頁數：	57
中文關鍵詞：	腸病毒71型、血纖維蛋白溶酶原、血纖維蛋白溶酶原基因剔除小鼠、細胞激素
外文關鍵詞：	Human enterovirus A71 species, Plasminogen (PLG), Plasminogen knock-out mice, cytokines
相關次數：	點閱：68 下載：0
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腸病毒A71型（EV-A71）是一種高致病性的微小RNA病毒，在兒童感染症之中會引起嚴重的手足口病（HFMD）或神經系統併發症。目前，腸病毒A71型的流行已造成了許多幼童罹患腦膜炎，在過去的二十年中也已有數千例幼兒因此而死亡。但迄今為止，並沒有特別有效的疫苗或治療方法可以預防或治療腸病毒A71型的感染。因此，目前仍需迫切尋找新的腸病毒A71型治療手段。在近期的研究之中，SCARB2和PSGL是腸病毒A71型的細胞受體。通過識別這些受體，病毒可以增加對宿主細胞的感染性。在我們的實驗室中利用醣蛋白質體的方式，鑑定出16種腸病毒A71型相互作用醣類蛋白可作為腸病毒A71型的新型結合受體，包括人類核仁蛋白（NCL）和血纖溶酶原（PLG）。除此之外，我們使用酵素結合免疫吸附分析法(ELISA)和表面等離子體共振（SPR），發現了腸病毒A71型直接與PLG結合的證據。這些證據強烈表明血纖溶酶原可以協調並幫助腸病毒A71型感染宿主細胞。在我的研究中，利用PLG knock-out (PLG-KO)小鼠（C57BL / 6）設計動物實驗模型監測生物體內MP4（EV-A71小鼠適應病毒株）感染。我們分析了EV-A71感染後的PLG-KO小鼠的臨床症狀和存活率。然後，測量了PLG-KO小鼠的中樞神經和肌肉中的病毒量並利用組織病理學觀察肌肉，脊髓，腦幹切片中的腸病毒A71型及腦膜炎病癥。我們的研究結果發現，去除PLG基因表現的小鼠不僅會表現出較輕微的臨床疾病症狀，而且在不同器官中會表現出較低的病毒量和腸病毒A71型抗體訊號。基於這些結果，我們認為血纖溶酶原可能涉及小鼠體內腸病毒A71型的結合和以及促進疾病發展。下一步，我們想要測定血纖溶酶原和腸病毒A71型免疫反應的作用。在不同的神經器官中觀察PLG-KO和野生型小鼠的細胞激素表現量。發現MCP-1在這兩隻小鼠的神經系統中最具有顯著差異。這些細胞激素在臨床上與腸病毒A71型感染後腦炎和肺水腫有關，暗示這兩種細胞激素和血纖溶酶原之間的交互作用可能影響腸病毒A71型感染後的炎症反應。我們的發現不僅證實了血纖溶酶原可能在體內腸病毒A71型發病機制中起重要作用的事實，而且還為治療腸病毒A71型感染提供了新的靶點。

Enterovirus A71 (EV-A71) is a highly pathogenic Picornaviridae that causes hand, foot, and mouth disease (HFMD) or severe neurological complications in children. Outbreaks of EV-A71 infection have cause several cases of aseptic meningitis and deaths in young children in last 2 decades. To date, few licensed vaccines exist against EV-A71, and there are no approved therapeutics for treatment. Therefore, there is an urgent need for a new treatment for EV-A71 infection. Recent research has confirmed that human scavenger receptor class B, member 2 (SCARB2), and P-selectin glycoprotein ligand-1 (PSGL1) are the cellular receptors for enterovirus A71 (EV-A71). By recognizing these receptors, the virus can increase infectivity to host cells. Our previous works employed glycoproteomic approaches to identify 16 types of EV-A71-interacting proteins as novel binding receptors for EV-A71, including human nucleolin (NCL) and plasminogen (PLG). By using ELISA and a surface plasmon resonance (SPR) assay, we found that EV-A71 can directly bind to PLG. These findings strongly suggest that PLG can be used as a coordinator to help spread EV-A71 infection. In this thesis, PLG knockout mice (C57BL/6) were used to monitor an MP4 (EV-A71 mouse adapted virus) infection in vivo. We analyzed the clinical scores and survival rates of EV-A71-infected PLG knockout and wild type mice. Then, we analyzed the viral load in the central nervous system and muscle of both types of mice. EV-A71 distribution in the muscle, spinal cord, and brain stem sections of the mice was observed through a histopathological examination. Our findings indicated that PLG-KO mice not only displayed lower clinical scores, but also showed a lower virus titer and IHC signal in different organs. Based on these results, we suggested that PLG might be involved in the binding and infection of EV-A71. In addition, we revealed the immune responses of EV-A71-infected PLG knockout and wild type mice. Cytokines levels of PLG-KO and wild-type mice were investigated in different nerve organs. We found that such cytokines, especially MCP-1, were significantly elevated in the nervous system of the mice. These cytokines are clinically related to encephalitis and pulmonary edema, which implied that the reaction of these cytokines and PLG may affect the inflammatory response after EV-A71 infection. Our findings not only confirm that PLG may play an important part in EV-A71 pathogenesis in vivo, but also provide a novel target for treating EV-A71 infection.

English Abstract III
Chinese Abstract VI
誌謝 VII
Table of content VIII
Figure Index XI
Table Index XII
Appendix Index XIII
Abbreviations XIV
Chapter 1. Introduction  1
1. Human enterovirus A71 (EV-A71) 1
1.1 Clinical symptoms and epidemiology 	1
1.2 Classification and structure 1
2. EV-A71 Receptors and attachment factors 2
3. Plasminogen (PLG) 4
3.1 Structure 4
3.2 Function 5
3.3 Relationship between PLG and viruses 6
4. Animal models 6
Chapter 2. Objective 8
Chapter 3. Materials and methods 10
1. Cell culture	10
2. Virus amplification 10
3. Plaque assay	10
4. Animal model	11
4.1 Infection	11
4.2 Genotyping	11
4.3 Clinical scores and survival rate	12
4.4 Viral load in tissues 12
5. Histopathological and immunohistochemical (IHC) staining. 13
6. Cytokine measurement	13
7. Statistical analysis	14
Chapter 4. Results 15
Previous studies 15
Establishing a PLG-KO mice animal model	15
Evaluation of the paralysis mechanism of observing protein quantification and tissue section 15
1. Total PLG protein expression was greater in the wild-type mice than in the PLG-KO mice 15
2. PLG deficiency increases the survival rates of mice infected with EV-A71 16
3.PLG deficiency decreases the virus titers in mice organ16
4.The disease progression of the PLG-KO and WT mice after infection with EV-A71 17
Immunologic response of PLG-KO mice by cytokine detection in the serum 18
Immunologic response of PLG-KO mice by cytokine detection in the spinal  cords 19
Chapter 5. Discussion 20
Cytokines response in the mice	21
PLG combines with other attachment factor in the EV-A71 infection. 22
EV-A71-infected PLG-KO mice models 23
Establish a new hPLG-Tg mice model to investigate EV-A71 infection. 24
Chapter 6. Conclusion	26
References 27
Figure 1. Establishing animal model of PLG-KO mice 50
Figure 2. Mouse endogenous plasminogen protein expression analyzed in the PLG-KO mice and wild type mice. 37
Figure 3. The clinical scores and survival rates of PLG knockout mice in EV-A71 infection 38
Figure 4. The viral load in central nervous and muscle of PLG knockout mice 19
Figure 5. Histopathological examination of muscle, spinal cord, brain stem  sections in two different mouse models.	40
Figure 6. Cytokine concentrations (pg/organ(g)) in the serum samples from the 2  groups of the mice including WT mice  and PLG-KO mice.	41
Figure 7. Cytokine concentrations (pg/organ(g)) of MCP-1 in the spinal cord from the 2 groups of the mice including WT mice and PLG-KO mice	42

Table 1. Genotyping conditions	43
Table 2. Comparison of MCP-1 cytokines level and clinical symptom in two mice 44

Appendix 1. Summary of the picornavirus life cycle 45
Appendix 2. Schematic view of EV-A71 activities in rhabdomyosarcoma cells	46
Appendix 3. Schematic of the enterovirus genome, the polyprotein products and their major functions.	47
Appendix 4. Mechanism of fibrinolysis	48
Appendix 5. X-ray crystal structure of closed plasminogen glycoform II 49
Appendix 6. List of EV71-interacting proteins identified by glycoproteomic approaches 50
Appendix 7. Schematic procedure of glycoproteomics approach 51
Appendix 8. The clinical scores of WT mice evaluated with different titers of MP4 52
Appendix 9. The binding of different genotypes of EV-A71 to RD cells. 53
Appendix 10. The protein-protein interaction was detected by SPR assay reader 54
Appendix 11. PLG facilitates EV71 binding to RD cells	55
Appendix 12. Knockdown of PLG attenuates EV71 binding to RD cells 56
Appendix 13. The association between PLG and NCL or Anx2	57

                                    

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