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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 伍安怡 | |
| dc.contributor.author | Ta-Chun Lin | en |
| dc.contributor.author | 林大鈞 | zh_TW |
| dc.date.accessioned | 2021-06-13T03:29:19Z | - |
| dc.date.available | 2011-08-04 | |
| dc.date.copyright | 2006-08-04 | |
| dc.date.issued | 2006 | |
| dc.date.submitted | 2006-07-28 | |
| dc.identifier.citation | Alvarez, C. P., Lasala, F., Carrillo, J., Muniz, O., Corbi, A. L., and Delgado, R. (2002). C-type lectins DC-SIGN and L-SIGN mediate cellular entry by Ebola virus in cis and in trans. J Virol 76, 6841-6844.
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E., Brizuela-Garcia, A., Heras-Chavarria, M., Flores-Langarica, A., et al. (2005). Dengue virus inoculation to human skin explants: an effective approach to assess in situ the early infection and the effects on cutaneous dendritic cells. Int J Exp Pathol 86, 323-334. Lin, Y. W., Wang, K. J., Lei, H. Y., Lin, Y. S., Yeh, T. M., Liu, H. S., Liu, C. C., and Chen, S. H. (2002). Virus replication and cytokine production in dengue virus-infected human B lymphocytes. J Virol 76, 12242-12249. Lozach, P. Y., Burleigh, L., Staropoli, I., Navarro-Sanchez, E., Harriague, J., Virelizier, J. L., Rey, F. A., Despres, P., Arenzana-Seisdedos, F., and Amara, A. (2005). Dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN)-mediated enhancement of dengue virus infection is independent of DC-SIGN internalization signals. J Biol Chem 280, 23698-23708. Ma, L., Jones, C. T., Groesch, T. D., Kuhn, R. J., and Post, C. B. (2004). 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G., Takahara, K., Umemoto, E., Yashima, Y., Matsubara, K., Matsuda, Y., Clausen, B. E., Inaba, K., and Steinman, R. M. (2001). Five mouse homologues of the human dendritic cell C-type lectin, DC-SIGN. Int Immunol 13, 1283-1290. Pinheiro, F. P., and Corber, S. J. (1997). Global situation of dengue and dengue haemorrhagic fever, and its emergence in the Americas. World Health Stat Q 50, 161-169. Powlesland, A. S., Ward, E. M., Sadhu, S. K., Guo, Y., Taylor, M. E., and Drickamer, K. (2006). Novel mouse homologs of human DC-SIGN: widely divergent biochemical properties of the complete set of mouse DC-SIGN-related proteins. J Biol Chem. Rigau-Perez, J. G., Clark, G. G., Gubler, D. J., Reiter, P., Sanders, E. J., and Vorndam, A. V. (1998). Dengue and dengue haemorrhagic fever. Lancet 352, 971-977. Scott, R. M., Nisalak, A., Cheamudon, U., Seridhoranakul, S., and Nimmannitya, S. (1980). Isolation of dengue viruses from peripheral blood leukocytes of patients with hemorrhagic fever. J Infect Dis 141, 1-6. Soilleux, E. J., Barten, R., and Trowsdale, J. (2000). DC-SIGN; a related gene, DC-SIGNR; and CD23 form a cluster on 19p13. J Immunol 165, 2937-2942. Steinman, R. M. (2000). DC-SIGN: a guide to some mysteries of dendritic cells. Cell 100, 491-494. Sumarmo, Wulur, H., Jahja, E., Gubler, D. J., Suharyono, W., and Sorensen, K. (1983). Clinical observations on virologically confirmed fatal dengue infections in Jakarta, Indonesia. Bull World Health Organ 61, 693-701. Takahara, K., Yashima, Y., Omatsu, Y., Yoshida, H., Kimura, Y., Kang, Y. S., Steinman, R. M., Park, C. G., and Inaba, K. (2004). Functional comparison of the mouse DC-SIGN, SIGNR1, SIGNR3 and Langerin, C-type lectins. Int Immunol 16, 819-829. Tassaneetrithep, B., Burgess, T. H., Granelli-Piperno, A., Trumpfheller, C., Finke, J., Sun, W., Eller, M. A., Pattanapanyasat, K., Sarasombath, S., Birx, D. L., et al. (2003). DC-SIGN (CD209) mediates dengue virus infection of human dendritic cells. 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Detection of dengue virus replication in peripheral blood mononuclear cells from dengue virus type 2-infected patients by a reverse transcription-real-time PCR assay. J Clin Microbiol 40, 4472-4478. Wu, L., Martin, T. D., Carrington, M., and KewalRamani, V. N. (2004). Raji B cells, misidentified as THP-1 cells, stimulate DC-SIGN-mediated HIV transmission. Virology 318, 17-23. Wu, Y. C. (1986). [Epidemic dengue 2 on Liouchyou Shiang, Pingtung County in 1981]. Zhonghua Min Guo Wei Sheng Wu Ji Mian Yi Xue Za Zhi 19, 203-211. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/32045 | - |
| dc.description.abstract | 登革熱病毒是一種由蚊子傳染的疾病，近年來登革熱已成為世界性的公衛問題，可是因缺乏好的動物模式，其致病及出血機制仍不清楚。因此，建立一個動物模式來進行這方面研究就成為不可或缺的前提。
人類DC-SIGN受體主要表現在人類樹突狀細胞上，已被報導可以辨認登革熱病毒並且幫助病毒進入細胞內。因此我假設小鼠細胞表現人類DC-SIGN受體便可以幫助登革熱病毒進入小鼠細胞內，進而造成病毒在小鼠細胞內繁殖。長遠來看，若假設成立，那麼我們便可以建立一隻轉殖基因小鼠表現此受體作為研究登革熱病毒感染致病機制的動物模式。 首先，我比較人類Raji細胞株與人類Raji細胞株表現人類DC-SIGN對於感染登革熱病毒所造成的差異。我發現當人類Raji細胞株在表現人類DC-SIGN後，可以成為登革熱病毒的宿主細胞。接著我建立一穩定表現人類DC-SIGN的小鼠B細胞株，藉由比較有表現人類DC-SIGN與不表現人類DC-SIGN的小鼠B細胞株在感染登革熱病毒後的結果，我發現有表現人類DC-SIGN的細胞株，可以在細胞中表現病毒的core基因及13kDa的病毒蛋白。同時自感染後12小時開始，在感染細胞株的培養液中，病毒core基因的數量持續上升。這些結果證明了登革熱病毒可以藉由人類DC-SIGN進入小鼠細胞，同時也可在細胞中進行繁殖。另一方面，我也觀察表現人類DC-SIGN的小鼠B細胞在感染登革熱病毒後的細胞反應。發現細胞在被登革熱病毒感染後，表現CD69、CD86和分泌TNF-α及IL-6蛋白質都有升高的現象。這些結果暗示登革熱病毒不但可以在有表現人類DC-SIGN的小鼠細胞內繁殖，同時也可以引發細胞反應。 此外我設計了一個載體 (pK14Tyr-PolIIhDC-SIGN-IN2B)，使得人類DC-SIGN基因可以受小鼠第二聚和脢促進子的驅動，以及被兩份隔離子所保護。在轉殖此載體進入人類293T細胞後，人類DC-SIGN受體可表現在細胞表面。接著此載體以顯微注射遞送到小鼠受精卵中，其子代以聚合脢鏈鎖反應篩選轉殖基因是否嵌入其基因體。我發現18隻子代中有兩隻小鼠之基因體有表現人類DC-SIGN基因。接著我以其中的一隻小鼠周邊血白血球做蛋白質表現分析，也發現人類DCSIGN受體有表現在70%細胞表面，這個結果證明了此載體的可用性。以後利用這一隻轉殖基因小鼠來研究登革熱病毒感染的致病機制是可期待的。 | zh_TW |
| dc.description.abstract | Dengue virus is an arthropod-borne flavivirus that causes dengue fever and heamorrhagic fever in humans. It is an emerging and volatile public health concern, but the pathogenic mechanism has not been elucidated. An animal model is needed to study the pathogenesis of dengue virus infection.
It has been reported that human C-type lectin DC-SIGN that is expressed on human monocyte-derived dendritic cells binds to dengue virus. Thus, it is my speculation that animals expressing hDC-SIGN will facilitate dengue virus entering target cells and allow virus replication. The long term goal of our laboratory is to generate transgenic mouse lines to study the immunopathogenic mechanism of dengue. As a first step to reach that goal, the first aim of my study was to investigate whether mouse cells expressing hDC-SIGN became more susceptible to dengue virus infection. Next, I designed and constructed a plasmid to generate hDC-SIGN transgenic mice for the study of dengue immunopathogenesis. First, I compared human B cell lines Raji and transfected Raji-DC-SIGN for their susceptibility to dengue virus infection and found that Raji-DC-SIGN cells were susceptible to dengue virus infection, verifying results reported in the literature. Later, I transfeced mouse B cell line M12 with hDC-SIGN and selected three stable clones, all with >90% of hDC-SIGN expression. Comparing hDC-SIGN expressing M12 with untrasnfected parental M12, I found that after infection dengue virus core gene mRNA and 13 kDa viral proteins were detected in hDC-SIGN-M12 but not in parental M12 at 12h. The virus copy numbers in the supernatants of hDC-SIGN-M12 culture also gradually increased at 12 h on after infection, indicating dengue virus replicates in the hDC-SIGN-transfected M12 cells. These results demonstrate that hDC-SIGN mediates dengue virus entry into mouse B cells and transfected mouse B cells support dengue virus replication. Furthermore, cellular response of hDC-SIGN-M12 to dengue virus was monitored. The results showed that infection by dengue virus upregulated the expressions of CD69 and CD86 and the production of TNF-α and IL-6 in hDC-SIGN-M12 cells. The results of these in vitro studies indicate that mouse cells can support the replication of and mount cellular responses to dengue virus, providing that hDC-SIGN is expressed. I went on to construct a plasmid (pK14Tyr-PolIIhDC-SIGN-IN2B) that hDC-SIGN is under the control of polymerase II promoter, followed by a polyA tail and two copies of insulators. In vitro study showed that 293T cells transfected with pK14Tyr-PolIIhDC-SIGN-IN2B plasmid expressed hDC-SIGN on the surface. Offspring of the fertilized eggs whose pronuclei were injected of the plasmid were screened for transgene expression. Screening of the genomic DNA by PCR, I found two transgenic founders carried the hDC-SIGN transgene and the peripheral blood leukocytes of one of them expressed hDC-SIGN on the cell surface. These results showed that the strategy of plasmid construction works. The transgenic progeny will be ready for the study of the immunopathogenic mechanisms of dengue in the near future. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T03:29:19Z (GMT). No. of bitstreams: 1 ntu-95-R93449002-1.pdf: 2046643 bytes, checksum: fa9d4f0ea691664c4ba069b8c4cd0999 (MD5) Previous issue date: 2006 | en |
| dc.description.tableofcontents | Abstract i
Abstract (Chinese) iii Chapter I. Introduction Part 1. Dengue virus and dengue 2 Part 2. DC-SIGN (CD209) 3 Part 3. Target for Pathogens 6 Part 4. Human B lymphocyte is susceptible for dengue virus 9 Part 5. The rationale to study human DC-SIGN in mediating dengue virus infection of mouse B lymphocytes 10 Chapter II. Materials and Methods Part 1. Experimental Procedures 12 1.1 Cell line 12 1.2 Whole cell extracts 12 1.3 Western blot 12 1.4 Total RNA extraction 13 1.5 RT-PCR and quantitative real-time PCR 14 1.6 Cell surface molecule staining and flow cytometric analysis 15 1.7 Cell surface staining to select stable clones of M12-hDC-SIGN cells 15 1.8 Costimulation molecules staining after cells infected with dengue virus 16 1.9 Intracellular cytokines staining 16 1.10 TNF-α ELISA assay 17 Part 2 Experimental Materials 18 Chapter III. Results Part 1. Expressing hDC-SIGN on human Raji cell line confers susceptibility to DV infection 26 1.1 Dengue viral capsid antigen and core gene expression are detected in Raji-DC-SIGN cells after infection 26 1.2 hDC-SIGN expressed Raji cells support dengue virus replication 27 Part 2. Dengue virus infection of mouse B cell line expressing hDC-SIGN 27 2.1 Selecion of stable hDC-SIGN expressing M12 clones 27 2.2 Dengu viral antigen and core gene expression in M12-hDC-SIGN cell lysates after infection 28 2.3 M12 cells expressing hDC-SIGN support dengue virus replication 29 Part 3. The cellular response of mouse B lymphocytes to DV infection 29 3.1 The expression of costimulatory molecules 29 3.2 The expression of cytokines 30 Chapter Ⅳ. Discussion 32 Reference 39 Figure Figure 1. Western blot analysis of DV antigen expression in Raji and Raji-DC-SIGN cell lines after DV infection. 47 Figure 2. Comparing DV infectivity in Raji and Raji-DC-SIGN cell lines. 49 Figure 3. Stable expression of hDC-SIGN in mouse M12 B cell line. 51 Figure 4. Comparing DV antigen expression in M12 and M12-hDC-SIGN cell lines. 53 Figure 5. Comparing DV infectivity in M12 and M12-hDC-SIGN cells. 55 Figure 6. M12-hDC-SIGN cells respond to DV infection by upregulation of CD69 and CD86 expression. 57 Figure 7. TNF-α gene expression and production are upregulated in M12-hDC-SIGN cells after DV infection. 60 Figure 8. IL-6 gene expression and production are upregulated in M12-hDC-SIGN cells after B cell activation. 62 Chapter Ⅴ. Appendix Part 1. Introduction 65 Part 2. Materials and Methods 67 2.1 Construction 67 2.2 Genotyping for candidates of transgenic mice 67 Part 3. Result 69 3.1 To establish a mammalian expression vector expressing hDC-SIGN 69 3.2 hDC-SIGN expression in mammalian cells 70 3.3 Generation of the hDC-SIGN transgenic mice 70 Part 4. Discussion 71 Figures 73 | |
| dc.language.iso | en | |
| dc.subject | 登革熱病毒 | zh_TW |
| dc.subject | DC-SIGN | en |
| dc.subject | dengue virus | en |
| dc.title | 登革熱病毒藉由人類DC-SIGN感染小鼠B淋巴球 | zh_TW |
| dc.title | Human DC-SIGN mediates dengue virus infection of mouse B lymphocytes | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 94-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 繆希椿,張雯 | |
| dc.subject.keyword | 登革熱病毒, | zh_TW |
| dc.subject.keyword | dengue virus,DC-SIGN, | en |
| dc.relation.page | 80 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2006-07-28 | |
| 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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