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系統識別號 U0026-0812200910240007
論文名稱(中文) 抗登革病毒非結構性蛋白1抗體在體外及體內 模式上病理角色之研究
論文名稱(英文) Studies on the Pathological Role of Antibodies Against Dengue Virus Nonstructural Protein 1 Both in Vitro and in Vivo
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 90
學期 2
出版年 91
研究生(中文) 邱淑貞
研究生(英文) Shu-Chen Chiu
學號 s4689112
學位類別 碩士
語文別 中文
論文頁數 89頁
口試委員 指導教授-林以行
口試委員-黎煥耀
口試委員-黃坤正
中文關鍵字 非結構性蛋白1  登革 
英文關鍵字 dengue virus  nonstructural protein 1 
學科別分類
中文摘要 中文摘要
登革病毒 (dengue virus, DV) 屬於黃熱病毒科的一員,其傳染方式是藉由埃及斑蚊或白線斑蚊所媒介。臨床上,感染登革病毒的病人會有不同嚴重程度的症狀產生,輕則典型的發燒 (dengue fever),重則會有出血熱 (dengue hemorrhagic fever; DHF),甚至休克 (dengue shock syndrome; DSS) 的現象產生。血小板減少症、血管病變及出血性症狀是DHF/DSS主要的病徵,雖然如此,DV造成DHF/DSS的致病機轉仍不清楚。本實驗室先前的研究顯示,登革第二型病毒非結構性蛋白1抗體 (anti-DV NS1) 可以交互結合至內皮細胞,並且會造成細胞功能喪失。進一步證實登革病人血清中anti-DV NS1抗體的確會和內皮細胞結合並造成細胞凋亡的結果。在本論文中,進一步探討anti-DV NS1在體內及體外病理的角色。我們純化構築於E. coli的DV2 NS1蛋白,並免疫小鼠進一步取得anti-DV NS1抗體。由免疫染色法證實anti-DV NS1的確會與人類微血管內皮細胞 (HMEC-1) 進行交叉結合反應,不僅如此,抗體亦可以結合至小鼠的血管內皮細胞。萃取內皮細胞的膜蛋白經由西方墨點法觀察其與anti-NS1抗體結合,結果顯示分子量大約在95、130及150 kDa的位置分別有結合的反應。此外,將HMEC-1給予anti-DV NS1處理1小時後,再繼續培養12或24小時,也可觀察到明顯的細胞凋亡現象產生。進一步探討細胞活化訊息傳遞的機轉,結果顯示內皮細胞在anti-DV NS1刺激之後會有IL-6、IL-8及MCP-1的表現,而RANTES並沒有產生。利用流式細胞儀的方式證實,HMEC-1在給予anti-DV NS1處理後,ICAM-1會被誘導出,而且其黏著性有增高結合PBMC的趨勢。除此之外,為了要瞭解anti-DV NS1在體內的致病機轉,我們被動給予BALB/c小鼠anti-DV NS1,發現小鼠血清中AST、ALT值會明顯上升,而由病理切片觀察可知,在肝細胞中除了有一些吞噬細胞的浸潤外,還會有細胞凋亡現象的產生。綜而言之,anti-DV NS1在DV感染的過程中的確參與了重要的致病機轉,而這種機轉似乎與自體免疫的產生有著密切的關係。
英文摘要 英文摘要
Dengue virus (DV), the member of Flaviviridae, are transmitted by Aedes aegypti or Aedes albopictus. In clinical, patients with DV infection show a wide range of disease severity from mild febrile illness as dengue fever to life-threatening dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS). Thrombocytopenia, vascular leakage, and hemorrhagic syndrome are the hallmarks of the DHF/DSS. However, the pathogenesis of DHF/DSS is poorly understood. Previous studies in our laboratory showed the endothelial cell dysfunction caused by antibodies (Abs) against DV nonstructural protein 1 (NS1). Anti-NS1 Abs from dengue patients cross-reacted with endothelial cells and caused endothelial cell apoptosis. In this study, anti-NS1 Abs were generated in mice and their effects on endothelial cells (HMEC-1) were examined. The cross-reactivity of anti-NS1 Abs with HMEC-1 cells was detected by immunostaining. The binding activity of anti-NS1 Abs was also observed in vascular endothelium of mouse vessel ex vivo. Western blot analysis demonstrated that proteins with molecular weights of approximately 95-, 130- and 150-kDa could be detected following the hybridization of anti-NS1 Abs with endothelial cell extract membrane fractions. Anti-NS1-induced HMEC-1 apoptosis could be observed when Abs were incubated with cells for 1 h, followed by 12 or 24 h further cultivation. The cytokine and chemokine production after anti-NS1 stimulation was also examined. Results showed that the expression of IL-6、IL-8 and MCP-1, but not RANTES, in endothelial cells increased after treatment with anti-NS1 Abs. Furthermore, we found that expression of ICAM-1 was induced and the adhesion ability of PBMC was upregulated after anti-NS1 stimulation. In the animal studies, the levels of AST and ALT in mouse sera increased after passive administration of anti-NS1 Abs. The pathological effects of anti-NS1 Abs in mouse liver revealed macrophages infiltratration and some cells undergoing apoptosis. Taken together, these findings may provide the evidence on the pathological role of anti-NS1 Abs in DV infection.
論文目次 目 錄
中文摘要 I
英文摘要 III
致謝 V
目錄 VI
圖目錄 IX
表目錄 XI
符號及縮寫索引表XII
序論 1
材料與方法 7
I. 材料 7
A. 實驗動物 7
B. 細菌株 7
C. 細胞株 7
D. 病毒株 8
E. 試劑 8
F. 耗材 11
G. 儀器 12
II. 方法 15
A. NS1重組蛋白之製備 15
(i) NS1重組蛋白之誘導表現 15
(ii) NS1重組蛋白的純化 15
B. SDS-PAGE膠體電泳 16
(i) SDS-PAGE 膠體電泳步驟 16
(ii) 以細菌為樣本時的處理 17
C. 蛋白質定量 17
D. NS1重組蛋白免疫小鼠及血清的製備 17
E. 細胞的分離與培養 18
(i) 繼代培養 18
(ii) 細胞保存 19
(iii) 細胞解凍 19
F. 抗體的製備 19
G. 抗體與血管內皮細胞株及靜脈內皮細胞的結合能力 20
(i) HMEC-1與抗體的結合能力 20
(ii) 血管壁與抗體的結合能力 20
H. 膜蛋白之分析 21
(i) 膜蛋白之製備 21
(ii) 西方墨點 21
I. 細胞凋亡之觀察 22
(i) TUNEL 22
(ii) Annexin V 22
J. Cytokine之細胞染色 22
K. RT-PCR 23
(i) RNA之萃取 23
(ii) RNA濃度之偵測 24
(iii) 反轉錄反應合成cDNA 24
(iv) PCR 24
(v) PCR核酸產物電泳 25
L. 酵素結合免疫吸附法 26
M. 細胞黏著的現象 26
N. 被動給予抗體之小鼠病理現象觀察 27
(i) 血清中生化成份的測定 27
(ii) 以HE stain觀察器官的病理變化 27
(iii) 以螢光染色觀察器官的病理變化 27
結果 29
A. NS1重組蛋白之製備 29
B. 在in vitro及ex vivo的情況下,anti-DV NS1抗體與內皮細胞之結合 29
C. Anti-DV NS1抗體與HMEC-1膜蛋白結合的位置 30
D. Anti-DV NS1抗體造成內皮細胞的凋亡 30
E. Anti-DV NS1抗體與HMEC-1結合引發細胞激素的釋放 31
F. Anti-DV NS1抗體誘導細胞黏著能力 31
G. 被動給予抗體小鼠血清中AST和ALT之偵測 32
H. 被動給予抗體小鼠血清中BUN之偵測 33
I. 被動給予抗體小鼠之肝臟病理變化 34
討論 35
參考文獻 41
表 51
圖 53
附錄 68
作者簡歷 74
參考文獻 參 考 文 獻
Anderson, R., S. Wang, C. Osiowy, and A. C. Issekutz. 1997. Activation of endothelial cells via antibody-enhanced dengue virus infection of peripherial blood monocytes. J. Virol. 71:4226.
Avirutnan, P., P. Malasit, B. Seliger, S. Bhakdi, and M. Husmann. 1998. Dengue virus infection of human endothelial cells leads to chemokine production, completement activation, and apoptosis. J. Immunol. 161:6338.
Bancroft, T. L. 1906. On the etiology of dengue fever. Med. Gaz. 25:17.
Bethell, D. B., K. Flobbe, C. X. Thanh Phuong, N. P. J. Day, P. T. Phuong, W. A. Buurman, M. J. Cardosa, N. J. White, and D. Kwiatkowski. 1998. Pathophysiologic and prognostic role of cytokines in dengue hemorrhagic fever. J. Infect. Dis. 177:778.
Bhamarapravati, N., P. Toochinda, and V. Boonyapaknavil. 1967. Pathology of Thailand haemorrhagic fever: a study of 100 autopsy cases. Ann. Trop. Med. Parasitol. 61:500.
Bhamarapravati, N. 1989. Hemostatic defects in dengue hemorrhagic fever. Rev. Infect. Dis. 11:826.
Bielefeldt-Ohmann, H. 1997. Pathogenesis of dengue virus diseases: missing pieces in the jigsaw. Trends Mocrobiol. 5:409.
Bokisch, V. A., F. H. Top, Jr., P. K. Russell, F. J. Dixon, and H. J. Muller-Eberhard. 1973. The potential pathogenic role of complement in dengue hemorrhagic shock syndrome. N. Engl. J. Med. 289:996.
Bonner, S. M., and M. A. O’Sullivan. 1998. Endothelial cell monolayers as a model system to investigate dengue shock syndrome. J. Virol. Methods 71:159.
Bordron, A, M., Dueymes, Y. Levy, C. Jamin, J. P. Leroy, J. C. Piette, Y. Shoenfeld, and P. Y. Youlnou. 1998. The binding of some human antiendothelial cell antibodies induces endothelial cell apoptosis. J. Clin. Invest. 101:2029.
Bray, M., and C. J. Lai. 1991. Dengue virus premembrane and membrane proteins elicit a protective immune response. Virology 185:505.
Bray, M., R. Men, and C. J. Lai. 1996. Monkeys immunized with intertypic chimeric dengue viruses are protected against wild-type virus challenge. J. Virol. 70: 4162.
Burke, T. 1968. Dengue haemorrhagic fever: a pathological study. Trans. R. Soc. Trop. Med. Hyg. 62:682.
Cammack, N., and E. A. Gould. 1986. Antigenic analysis of yellow fever virus glycoproteins: use of monoclonal antibodies in enzyme-linked immunosorbent assays. J. Virol. Methods 13:135.
Cardiff, R. D., W. E. Brandt, T. G. McCloud, D. Shapiro, and P. K. Russell. 1971. Immunological and biophysical separation of dengue-2 antigen. J. Virol. 7:15.
Cardiff, R. D., and J. K. Lund. 1976. Distribution of dengue-2 antigen by electron immunocytochemistry. Infect. Immun. 13:1699.
Cardosa, M. J. 1998. Dengue vaccine design: issues and challenges. Br. Med. Bull. 54: 395.
Chambers, T. J., D. W. McCourt, and C. M. Rice. 1990. Production of yellow fever virus protein in infected cells: identification of discrete polyprotein species and analysis of cleavage. Virology 177:159.
Chaturvedi, U. C., E. A. Elbishbishi, R. Agarwal, R. Raghupathy, R. Nagar, R. Tandon, A. S. Pacsa, O. I. Younis, and F. Azizieh. 1999. Sequential production of cytokines by dengue virus-infected human peripheral blood leukocyte cultures. J. Med. Virol. 59:335.
Chaturvedi, U. C., E. A. Elbishbishi, R. Agarwal, and A. S. Mustafa. 2001. Cytotoxic factor-autoantibodies: possible role in the pathogenesis of dengue haemorrahgic fever. FEMS Immunol. Med. Microbiol. 30:181.
Chen, Y., T. Maguire, R. E. Hileman, J. R. Fromm, J. D. Esko, R. J. Linhardt, and R. M. Marks. 1997. Dengue virus infectivity depends on envelope protein binding to target cell heparan sulfate. Nature Med. 8:866.
Chua, M. N., C. Molanida, R. Guzman, and F. Laberuza. 1993. Prothrombin time and partial thromboplastin time as a predictor of bleeding in patients with dengue hemorrhagic fever. Southeast Asian J. Trop. Med. Pub. Hlth. 25:65.
Despres, P., M. Flamand, P. E. Ceccaldi, and V. Deubel. 1996. Human isolates of dengue type 1 virus induce apoptosis in mouse neuroblastoma cells. J. Virol. 70:4090.
Despres, P., M. Frenkiel, P. E. Ceccaldi, C. Duarte dos Santos, and V. Deubel. 1998. Apoptosis in mouse central nervous system in response to infection with mouse-neurovirulent dengue viruses. J. Virol. 72:823.
Falconar, A. K. I. 1997. The dengue virus nonstructural-1 protein (NS1) generates antibodies to common epitopes on human blood clotting, integrin/adhesin protein and binds to human endothelial cells: potential implications in haemorrahgic fever pathogenesis. Arch. Virol. 142:897.
Falgout, B., R. Chanock, and C. J. Lai. 1989. Proper processing of dengue virus nonstructural glycoprotein NS1 requires the N-terminal hydrophobic signal sequence and the downstream nonstructural protein NS2A. J. Virol. 63:1852.
Falgout, B., M. Bray, J. J. Schlesinger, and C. J. Lai. 1990. Immunization of mice with recombinant vaccinia virus expressing authentic dengue virus nonstructural protein NS1 protects against lethal dengue virus encephalitis. J. Virol. 64:4356.
Gagnon, S. J., F. A. Ennis, and A. L. Rothman. 1999. Bystander target cell lysis and cytokine production by dengue virus-specific human CD4+ cytotoxic T-lymphocyte clones. J. Virol. 73:3623.
Gubler, D. J. 1998. Dengue and dengue haemorrahgic fever. Clin. Mocrobiol. Rev. 11:480.
Gunther, W., B. R. Valerie, R. C. Grham, E. R. Terence, and S. Victor. 1988. Evidence that the mature form of Flavivirus nonstructural protein NS1 in dimer. Virology 162:187.
Gunther, W., S, E, Maxwell., C, Ruemmler, and V, Stollar. 1989. Newly synthesized dengue-2 virus nonstructural protein NS1 is a soluble protein but becomes partially hydrophobic and membrane-associated after dimerization. Virology 171:302.
Halstead, S. B. 1970. Observations related to pathogenesis of dengue hemorrhagic fever. VI. Hypotheses and discussion. Yale J. Biol. Med. 42:350.
Halstead, S. B. 1979. In vivo enhancement of dengue virus infection in rhesus monkeys by passively transferred antibody. J. Infect. Dis. 140:527.
Halstead, S. B. 1988. Pathogenesis of dengue: challenges to molecular biology. Science 239:476.
Halstead, S. B. 1989. Antibody, macrophages, dengue virus infection, shock and hemorrhage: a pathogenetic casade. Rev. Infect. Dis. 11:830.
Hathirat P., P. Isarangkura, T. Srichaikul, C. Survatte, and C. Mitrakul. 1993. Abnormal hemostasis in dengue hemorrhagic fever. Southeast Asian J. Trop. Med. Pub. Hlth. 24:80.
Hayes, E. B., and D. J. Gubler. 1992. Dengue and dengue haemorrhagic fever. Pediatr. Infect. Dis. J. 11:311.
Henchal, E. A., L. S. Henchal, and J. J. Schlesinger. 1988. Synergistic interactions of anti-NS1 monoclonal antibodies protect passively immunized mice from lethal challenge with dengue-2 virus. J. Gen. Virol. 209:2101.
Henchal, E. A., and J. R. Putnak. 1990. The dengue virus. Clin. Micro. Rev. 3:376.
Huang, J. H., J. J. Wey, Y. C. Sun, C. Chin, L. J. Chien, and Y. C. Wu. 1999. Antibody responses to an immunodominant nonstructural 1 synthetic peptide in patients with dengue fever and dengue haemorrahgic fever. J. Med. Virol. 57:1.
Huang, K. J., S. Y. J. Li, S. C. Chen, H. S. Liu, Y. S. Lin, T. M. Yeh, C. C. Liu, and H. Y. Lei. 2000. Manifestation of thrombocytopenia in dengue-2-virus-infected mice. J. Gen. Virol. 81:2177.
Innis, B. L. 1995. Dengue and dengue hemorrhagic fever. In: Porterfield JS, editor. Kass handbook of infectious diseases: exotic viral diseases. London: Chapman and Hall. p 103.
Jacob, M. G., P. J. Robinson, C. Bletchly, J. M. Mackenzie, and P. R. Young. 2000. Dengue virus nonstructural protein 1 is expressed in a glycosyl-phosphatidylinositol-linked form that is capable of signal transduction. FASEB J. 14:1603.
Kalayanarooj, S., D. W. Vaughn, S. Nimmannitya, S, Green, S. Suntayakorn, N. Kunentrasai, W. Viramitrachai, S. Ratanachueke, S. Kiatpolpoj, B. L. Innis, A. L. Rothman, A. Nisalak, and F. A. Ennis. 1997. Early clinical and laboratory indicators of acute dangue illness. J. Infect. Dis. 176:313.
Kaufman, B. M., P. L. Summers, D. R. Dubois, and K. H. Eckels. 1987. Monoclonal antibodies against dengue-2 virus E-glycoprotein protect mice against lethal dengue infection. Am. J. Trop. Med. Hyg. 36:427.
King, C. A., J. S. Marshall, H. Alshurafa, and R. Anderson. 2000. Release of vasoactive cytokines by antibody-enhanced dengue virus infection of a human mast cell/basophil line. J. Virol. 74:7146.
Kochel, T., S. J. Wu, K. Raviprakash, P. Hobart, S. Hoffman, K. Porter, and C. Hayes. 1997. Inoculation of plasmids expressing the dengue-2 envelope gene elicit neutralizing antibodies in mice. Vaccine 15:547.
Kuhn, R. J., W. Zhang, M. G. Rossmman, S. V. Pletnev, J. Corver, E. Lenches, C. T. Johnes, S. Mukhopadhyay, P. R. Chipman, E. G. Strauss, T. S. Baker, and J. H. Strauss. 2002. Structure of dengue virus: implications for flavivirus organization, maturation and fusion. Cell 108:717.
Kuo, C. H., D. I. Tai, C. S. Chang-Chien, C. K. Lan, S. S. Chiou, and Y. F. Liaw. 1992. Liver Biochemical tests and dengue fever. Am. J. Trop. Med. Hyg. 47:265.
Kurane, I., B. L. Innis, A. Nisalak, C. Hoke, S. Nimmannitya, A. Meager, and F. A. Ennis. 1989. Human T cell responses to dengue virus antigen: proliferative responses and interferon gamma production. J. Clin. Invest. 83:506.
Kurane, I., A. L. Rothman, P. G. Livingston, S. Green, S. J. Gagnon, J. Janus, B. L. Innis, S. Nimmannitya, A. Nisalak, and F. A. Ennis. 1994. Immunopathologic mechanisms of dengue hemorrhagic fever and shock syndrome. Arch. Virol. Suppl. 9:59.
Lei, H. Y., T. M. Yeh, H. S. Liu, Y. S. Lin, S. H. Chen, and C. C. Liu. 2001. Immunopathogenesis of dengue virus infection. J. Biomed. Sci. 8:377.
Leitmeyer, K. C., D. W. Vaughn, D. M. Watts, R. Salas, I. Villalobos de Chacon, C. Ramos, and R. Rico-Hesse. 1999. Dengue virus structural differences that correlate with pathegenesis. J. Virol. 73:4738.
Lin, Y. L., C. C. Liu, H. Y. Lei, T. M. Yeh, Y. S. Lin, R. M. Y. Chen, and H. S. Liu. 2000. Infection of five human liver cell lines by dengue-2 virus. J. Med. Virol. 60:425.
Lin, Y. L., C. C. Liu, J. I. Chuang, H. Y. Lei, T. M. Yeh, Y. S. Lin, Y. H. Huang, and H. S. Liu. 2000b. Involvement of oxidative stress, NF-IL-6, and RANTES expression in dengue-2-virus-infected human liver cells. Virology 276:114.
Lin, Y. L., L. K. Chen, C. L. Liao, C. T. Yeh, S. H. Ma, J. L. Chen, Y. L. Huang, S. S. Chen, and H. Y. Chiang. 1998. DNA immunization with Japanese encephalitis virus nonstructural protein NS1 elicit protective immunity in mice. J. Virol. 72:191.
Littaua, R., I. Kurane, and F. A. Ennis. 1990. Human IgG receptor II mediates antibody-dependent enhancement of dengue virus infection. J. Immunol. 144:3183.
Mackenzie, J. M., M. K. Jones, and P. R. Young. 1996. Immunolocalization of the dengue virus nonstructural glycoprotein NS1 suggests a role in viral RNA replication. Virology 220:232.
Mady, B. J., D. V. Erbe, I. Kurane, M. W. Fanger, and F. A. Ennis. 1991. Antibody-dependent enhancement of dengue virus infection mediated by bispecific antibodies against cell surface molecules other than Fcγ receptors. J. Immunol. 147:3139.
Malasit, P. 1987. Complement and dengue hemorrhagic fever/shock syndrome. Southeast Asian J. Trop. Med. Pub. Hlth. 18:316.
Mangada, M. N. M., and A. Igarashi. 1998. Molecular and in vitro analysis of eight dengue type 2 viruses isolated from patients exhibiting different disease severities. Virology 244:458.
Marianneau. P., A. Cardona, L. Edelman, V. Deubel, and P. Despres. 1997. Dengue virus replication in human hepatoma cells activates NF-B which in turn induces apoptotic cell death. J. Virol. 71:3244.
Mason, P. W. 1989. Maturation of Japanese encephalitis virus glycoproteins produced by infected mammalian and mosquito cells. Virology 169:354.
Mathew, A., I. Kurane, S. Green, D. W. Vaughn, S. Kalayanarooj, S. Suntayakorn, F. A. Ennis, and A. L. Rothman. 1999. Impaired T cell proliferation in acute dengue infection. J. Immunol. 162:5609.
Monath, T. P. 1994. Dengue: the risk to developed and developing countries. Proc. Natl. Acad. Sci. USA 91:2395.
Morens, D. M. 1994. Antibody-dependent enhancement of infection and the pathogenesis of viral disease. Clin. Infec. Dis. 19:500.
Mukerjee, R., U. C. Chaturvedi, and R. Dhawan. 1995. Dengue virus-induced human cytotoxic factor: production by peripheral blood leukocytes in vitro. Clin. Exp. Immunol. 102:262.
Putnak, R., D. A. Barvir, J. M. Burrous, D. R. Dubois, V. M., Hoke, C. H. D. Andrea, J. C. Sadoff, and K. H. Eckels. 1996. Development of a purified, inactivated, dengue-2 virus vaccine prototype in Vero cells: immunogenicity and protection in mice and rhesus monkeys. J. Infect. Dis. 174:1176.
Putnak, J. R., N. Kanesa-Thasan, and B. R. Innis. 1997. A putative cellular receptor for dengue viruses. Nature Med. 3:828.
Raghupathy, R., U. C. Chaturvedi, H. Al-Sayer, E. A. Albishbishi, R. Agarwal, R. Nagar, S. Kapoor, A. Misra, A. Mathur, H. Nusrat, F. Azizieh, M. A. Y. Kahn, and A. S. Mustafa. 1998. Elevated levels of IL-8 in dengue hemorrhagic fever. J. Med. Virol. 56:280.
Rhandolph, V. B., G. Winkler, and V. Stollar. 1990. Acidotropic amines inhibit proteolytic processing of flavivirus prM protein. Virology 174:450.
Rico-Hesse, R., L. M. Harrison, R. A. Salas, D. Tovar, A. Nisalak, C. Ramos, J. Boshell, M. T. R. de Mesa, R. M. R. Nogueira, and A. Travassos da Rosa. 1997. Origin of dengue type 2 viruses associated with increases pathogenicity in the Americans. Virology 230:244.
Rigau-Perez, J. G., G, G, Clark., D, J, Gubler., P, Reiter., E, J, Sanders, and A, V, Vorndam. 1998. Dengue and dengue haemorrahgic fever. Lancet 352:971.
Rose, N. R. 1998. The role of infection in the pathogenesis of autoimmune disease. Semin. Immunol. 10:5.
Rosen, L. 1977. The emperor’s new clothes revisited, or reflections on the pathogenesis of dengue hemorrhagic fever. Am. J. Trop. Med. Hyg. 26:337.
Rosen, L., M. M. Khin, and U. T. 1989. Recovery of virus from the liver of children with fetal dengue: reflections on the pathogenesis of the disease and its possible analogy with that of yellow fever. Res. Virol. 140:351.
Rothman, A. L., and F. A. Ennis. 1999. Immunopathogenesis of dengue hemorrhagic fever. Virology 257:1.
Ruangjirachuporn, W., S. Boonpucknavig, and S. Nimmannitya. 1979. Circulating immune complexes in serum from patients with dengue virus haemorrhagic fever. Clin. Exp. Immunol. 36:46.
Sabin, A. B. 1952. Research on dengue during World War II. Am. J. Trop. Med. Hyg.1:30.
Shaio, M. F., F. Y. Chang, and S. C. Hou. 1992. Complement pathway activity in serum from patients with classical dengue fever. Trans. Roy. Soc. Trop. Med. Hyg. 86:672.
Simmons, J. S., J. H. St. John, and F. H. K. Reynolds. 1931. Experimental studies of dengue. Philipp. J. Sci. 44:1.
Stohlman, S. A., C. L. Wisseman, O. P. Jr. Eylar, and D. J. Silverman. 1975. Dengue virus-induced modifications of host cell membranes. J. Virol. 16:1017.
van Gorp, E. C. M., C. Suharti, H. ten Cate, W. M. V. Dolmans, J. W. M. van der Meer, J. W. ten Cate, and D. P. M. Brandjes. 1999. Review: infectious diseases and coagulation disorders. J. Infect. Dis. 180:176.
Vaughn, D. W., C. H. Jr. Hoke, S. Yoksan, R. LaChance, B. L. Innis, R. M. Rice, and N. Bhamarapravati. 1996. Testing of a dengue 2 live-attenuated vaccine (strain 16681 PDK 53) in ten American volunteers. Vaccine 14:329.
Vaughn, D. W., S. Green, S. Kalayanarooj, B. L. Innis, S. Nimmannitya, S. Suntayakorn, T. P. Endy, B. Raengsakulrach, A. L. Rothman, F. A. Ennis, and A. Nisalak. 2000. Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity. J Infect. Dis. 181:2.
Velzing, J., J. Groen, M. T. Drouet, G. van Amerongen, C. Copra, A. D. M. E. Osterhaus, and V. Deubel. 1999. Induction of protective immunity against dengue virus type 2: comparison of candidate live attenuated and recombinant vaccines. Vaccine 17:1312.
Wang, L. Y., W. Y. Chang, S. N. Lu, and T. P. Chen. 1990. Sequential changes of serum transaminase and abnormal sonography in patients with suspected dengue fever. Kao Hsiung I Hsueh Ko Hsueh Tsa Chih 6:483.
Wang, S., R. He, J. Patarapotikul, B. L. Innis, and R. Anderson. 1995. Antibody-enhanced binding of dengue-2 virus to human platelets. Virology 213: 254.
吳盈昌. 1986. 1981年屏東縣琉球鄉之第二型登革熱流行。 中華微免雜誌 19:203.
行政院衛生署. 2000. 台閩地區法定傳染病及報告傳染病個案報告表。疫情報導.16:155.
鄭曲真. 2001. 國立成功大學醫學院微生物及免疫學研究所碩士論文。於動物模式研究登革病毒非結構性蛋白1抗體造成的病理影響。
林秋烽. 2002. 國立成功大學醫學院基礎醫學研究所博士論文.登革病毒感染產生自體抗體所引發的病理效應。
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