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系統識別號 U0026-2108201220541300
論文名稱(中文) 以小鼠模式探討抗C端修飾過之登革病毒非結構性蛋白1抗體的保護效果
論文名稱(英文) Study on the protective effects of antibodies against C-terminal region-modified dengue virus nonstructural protein 1 in mouse model
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 100
學期 2
出版年 101
研究生(中文) 張育菖
研究生(英文) Yu-Chang Chang
學號 s46994015
學位類別 碩士
語文別 英文
論文頁數 65頁
口試委員 指導教授-林以行
口試委員-葉才明
口試委員-林秋烽
口試委員-羅柏安得森
中文關鍵字 登革病毒  非結構性蛋白1  分子相似性  疫苗 
英文關鍵字 dengue virus  nonstructural protein 1  molecular mimicry  vaccine 
學科別分類
中文摘要 登革病毒 (dengue virus; DV) 是一種由蚊子所傳播的病毒,感染病人所造成的臨床症狀包括輕微的登革熱 (dengue fever; DF) 以及嚴重可能會致死的登革出血熱 (dengue hemorrhagic fever; DHF) 和登革休克症 (dengue shock syndrome; DSS)。在病人身上所出現的臨床症狀主要包括血管病變滲漏、血小板低下、出血時間延長以及大量細胞激素的產生。每年都有超過五千萬的登革感染病例,然而至今仍舊未研發出良好的抗病毒藥物以及疫苗可供使用。實驗室先前研究顯示,抗登革病毒非結構性蛋白1 (NS1) 抗體會交叉反應到人類的內皮細胞以及血小板,導致內皮細胞凋亡以及血小板凝集機制異常。依據蛋白質體學序列分析顯示NS1蛋白質之C端序列與自體抗原有高度相似性,考量以NS1為疫苗發展的安全性,我們將具有交互作用的抗原片段 (胺基酸271-352) 去除,產生了名為C NS1之蛋白質,另外也將此去除的片段由日本腦炎病毒 (JEV) NS1蛋白質之C端置換成名為DJ NS1之蛋白質。過去實驗室研究結果顯示,抗C NS1以及抗DJ NS1抗體對人類內皮細胞以及血小板的交叉反應能力較抗DV NS1抗體低。我們進一步於對DV更有感受性之STAT1-/-小鼠建立起DV感染的動物模式,實驗結果顯示,DV2感染STAT1-/-小鼠會造成小鼠出血時間延長、脾臟腫大以及大量細胞激素的產生。進一步於此動物模式觀察抗體治療性效果,結果指出,抗C NS1以及抗DJ NS1抗體能有效抑制由DV2感染所造成之小鼠出血時間延長以及與疾病嚴重程度相關之血清介白素 6 (IL-6) 以及巨噬細胞發炎蛋白質1 (MIP-1) 的產生。此外,抗C NS1以及抗DJ NS1抗體也被證實能有效降低由另一血清型登革病毒DV3感染所造成之小鼠出血時間延長、單核球趨化蛋白質1 (MCP-1)之產量以及巨噬細胞的浸潤程度。綜合以上結果,抗C NS1以及抗DJ NS1抗體不僅能提供同一血清型病毒感染治療性效果,對於不同血清型病毒的感染也提供一定的治療性效果,這也提供了登革疫苗發展所需之重要資訊。
英文摘要 Dengue virus (DV) is a mosquito-transmitted virus which may cause dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. Dengue patients show symptoms with plasma leakage, thrombocytopenia, bleeding tendency, and elevated cytokines. Over 50 million cases of DV infection occur each year, but there is still no approved antiviral treatment or vaccine available. Our previous studies showed that antibodies (Abs) against DV nonstructural protein 1 (NS1) cross-reacted with human endothelial cells and platelets and induced endothelial cell apoptosis and platelet dysfunction. Based on sequence analysis, the C-terminal region of DV NS1 protein contains homologous sequences with self-antigens. For safety concerns of vaccine development, we generated a C-terminal region (amino acid 271-352)-truncated DV NS1 protein or replaced the C-terminal region with JEV NS1 protein, designated C NS1 and DJ NS1, respectively. Anti-C NS1 Abs and anti-DJ NS1 Abs showed lower binding activity to human endothelial cells and platelets than that of anti-DV NS1 Abs. We further established a DV infection model in STAT1-/- mice which are more susceptible to DV as compared with the wild-type mice. Results showed that DV infection in STAT1-/- mice caused prolonged bleeding time, splenomegaly, and elevated levels of serum cytokines and chemokines. The therapeutic effects of anti-C NS1 Abs and anti-DJ NS1 Abs were further investigated in this mouse model. DV2-infected mice treated with anti-C NS1 Abs and anti-DJ NS1 Abs showed significant reduction of prolonged bleeding time and serum interleukin-6 and macrophage inflammatory protein-1 production, which were associated with disease severity. In addition, anti-C NS1 Abs and anti-DJ NS1 Abs also reduced DV3-induced prolonged bleeding time and monocyte chemotactic protein-1 production both in serum and local infection sites. Furthermore, macrophage infiltration to the local infection site was also inhibited in DV3-infected mice by treatment with anti-C and anti-DJ NS1 Abs. Taken together, these studies show not only the therapeutic effects of anti-C and anti-DJ NS1 Abs in DV2-infected mice but also cross-protective effects in DV3-infected mice. The results also provide important information for DV vaccine development.
論文目次 Chinese Abstract I
Abstract II
Acknowledgement IV
Contents V
Table and Figure List VIII
Abbreviations X
Introduction 1
Characteristics of dengue virus 1
Life cycle and target cells of dengue virus 3
Epidemiology of dengue virus 4
Clinical symptoms, classification, and diagnosis of dengue disease 5
The pathogenesis of dengue virus infection 7
Animal models of dengue virus infection 12
Vaccine development for dengue virus 13
Objective and Specific Aims 15
1. Preparation of Abs against C-terminal region-modified DV NS1 proteins and study of their protective effects. 16
2. Evaluation of the therapeutic effects of anti-C NS1 and anti-DJ NS1 Abs in DV2-infected STAT1-/- mice. 16
3. Investigation of the cross-therapeutic effects of anti-C NS1 and anti-DJ NS1 Abs in DV3-infected STAT1-/- 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 22
A-8 Consumables 23
A-9 Instruments 24
B. Methods 25
B-1 Antibody titer determination 25
B-2 Mouse tail bleeding time determination 25
B-3 Cell cultures 25
B-4 Plaque assay 26
B-5 Infection of endothelial cells with DV2 26
B-6 Flow cytometry 26
B-7 Western blotting 27
B-8 Histopathology 27
B-9 Animal protection model 27
B-10 Detection of serum cytokine levels 28
B-11 Detection of serum chemokine levels 28
B-12 Immunohistochemistry staining 28
B-13 Statistics 29
Results 30
1. Preparation of Abs against C-terminal region-modified DV NS1 proteins and study of their protective effects. 30
1.1 Preparation of the DV NS1, JEV NS1, C NS1, and DJ NS1 proteins. 30
1.2 Preparation of Abs against DV NS1, JEV NS1, C NS1, and DJ NS1 proteins. 30
1.3 Anti-C NS1 Abs can recognize NS1 protein expressed on DV-infected endothelial cells. 31
2. Evaluation of the therapeutic effects of anti-C NS1 and anti-DJ NS1 Abs in DV2-infected STAT1-/- mice. 31
2.1 A DV-infection model in STAT1-/- mice. 31
2.2 Anti-C and anti-DJ NS1 Abs reduce DV2-induced prolonged bleeding time. 32
2.3 Anti-C and anti-DJ NS1 Abs reduce DV2-induced cytokine and chemokine production in STAT1-/- mice. 33
3. Investigation of the cross-therapeutic effects of anti-C NS1 and anti-DJ NS1 Abs in DV3-infected STAT1-/- mice. 34
3.1 DV3-infected STAT1-/- mice show similar pattern as DV2-infected STAT1-/- mice of prolonged bleeding time and cytokine and chemokine production. 34
3.2 Anti-C and anti-DJ NS1 Abs reduce DV3-induced prolonged bleeding time. 34
3.3 Anti-C and anti-DJ NS1 Abs may reduce serum cytokine and chemokine production in DV3-infected STAT1-/- mice. 35
3.4 Anti-C and anti-DJ NS1 Abs reduce MCP-1 production, both in serum and local infection sites, and macrophage infiltration. 35
Discussion 36
References 42
Table and Figures 53
參考文獻 Ackermann, M., and R. Padmanabhan. 2001. De novo synthesis of RNA by the dengue virus RNA-dependent RNA polymerase exhibits temperature dependence at the initiation but not elongation phase. J Biol Chem 276 (43):39926-39937.
Anderson, R., et al. 1997. Activation of endothelial cells via antibody-enhanced dengue virus infection of peripheral blood monocytes. J Virol 71 (6):4226-4232.
Avirutnan, P., et al. 2006. Vascular leakage in severe dengue virus infections: a potential role for the nonstructural viral protein NS1 and complement. J Infect Dis 193 (8):1078-1088.
Avirutnan, P., et al. 2007. Secreted NS1 of dengue virus attaches to the surface of cells via interactions with heparan sulfate and chondroitin sulfate E. PLoS Pathog 3 (11):e183.
Avirutnan, P., et al. 2010. Antagonism of the complement component C4 by flavivirus nonstructural protein NS1. J Exp Med 207 (4):793-806.
Bashyam, H. S., et al. 2006. Dengue virus-reactive CD8+ T cells display quantitative and qualitative differences in their response to variant epitopes of heterologous viral serotypes. J Immunol 176 (5):2817-2824.
Basu, A., and U. C. Chaturvedi. 2008. Vascular endothelium: the battlefield of dengue viruses. FEMS Immunol Med Microbiol 53 (3):287-299.
Beltramello, M., et al. 2010. The human immune response to Dengue virus is dominated by highly cross-reactive antibodies endowed with neutralizing and enhancing activity. Cell Host Microbe 8 (3):271-283.
Benarroch, D., et al. 2004. The RNA helicase, nucleotide 5'-triphosphatase, and RNA 5'-triphosphatase activities of Dengue virus protein NS3 are Mg2+-dependent and require a functional Walker B motif in the helicase catalytic core. Virology 328 (2):208-218.
Bente, D. A., et al. 2010. Pathogenesis and immune response of Crimean-Congo hemorrhagic fever virus in a STAT-1 knockout mouse model. J Virol 84 (21):11089-11100.
Bozza, F. A., et al. 2008. Multiplex cytokine profile from dengue patients: MIP-1beta and IFN-gamma as predictive factors for severity. BMC Infect Dis 8:86-96.
Brown, M. G., et al. 2011. Dengue virus infection of mast cells triggers endothelial cell activation. J Virol 85 (2):1145-1150.
Brown, M. G., et al. 2009. Dramatic caspase-dependent apoptosis in antibody-enhanced dengue virus infection of human mast cells. J Leukoc Biol 85 (1):71-80.
Carlos, C. C., et al. 2005. Comparison of clinical features and hematologic abnormalities between dengue fever and dengue hemorrhagic fever among children in the Philippines. Am J Trop Med Hyg 73 (2):435-440.
Chaturvedi, U. C., et al. 1999. Sequential production of cytokines by dengue virus-infected human peripheral blood leukocyte cultures. J Med Virol 59 (3):335-340.
Chau, T. N., et al. 2008. Dengue in Vietnamese infants--results of infection-enhancement assays correlate with age-related disease epidemiology, and cellular immune responses correlate with disease severity. J Infect Dis 198 (4):516-524.
Chen, H. C., et al. 2007. Both virus and tumor necrosis factor alpha are critical for endothelium damage in a mouse model of dengue virus-induced hemorrhage. J Virol 81 (11):5518-5526.
Chen, M. C., et al. 2009. Deletion of the C-terminal region of dengue virus nonstructural protein 1 (NS1) abolishes anti-NS1-mediated platelet dysfunction and bleeding tendency. J Immunol 183 (3):1797-1803.
Chen, S. T., et al. 2008. CLEC5A is critical for dengue-virus-induced lethal disease. Nature 453 (7195):672-676.
Cheng, H. J., et al. 2009. Proteomic analysis of endothelial cell autoantigens recognized by anti-dengue virus nonstructural protein 1 antibodies. Exp Biol Med (Maywood) 234 (1):63-73.
Chou, W. S. 2011. Study on the protective effects of chimeric dengue virus nonstructural protein 1 antibodies both in vitro and in active immunization mouse model. Master thesis of Science in Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University.
Chung, K. M., et al. 2006. Antibodies against West Nile Virus nonstructural protein NS1 prevent lethal infection through Fc gamma receptor-dependent and -independent mechanisms. J Virol 80 (3):1340-1351.
Chungue, E., et al. 1994. Correlation between detection of plasminogen cross-reactive antibodies and hemorrhage in dengue virus infection. J Infect Dis 170 (5):1304-1307.
Clyde, K., and E. Harris. 2006. RNA secondary structure in the coding region of dengue virus type 2 directs translation start codon selection and is required for viral replication. J Virol 80 (5):2170-2182.
Coller, B. A., and D. E. Clements. 2011. Dengue vaccines: progress and challenges. Curr Opin Immunol 23 (3):391-398.
Cologna, R., and R. Rico-Hesse. 2003. American genotype structures decrease dengue virus output from human monocytes and dendritic cells. J Virol 77 (7):3929-3938.
Costa, S. M., et al. 2007. DNA vaccines against dengue virus based on the ns1 gene: the influence of different signal sequences on the protein expression and its correlation to the immune response elicited in mice. Virology 358 (2):413-423.
de-Oliveira-Pinto, et al. 2012. Profile of circulating levels of IL-1Ra, CXCL10/IP-10, CCL4/MIP-1beta and CCL2/MCP-1 in dengue fever and parvovirosis. Mem Inst Oswaldo Cruz 107 (1):48-56.
Dejnirattisai, W., et al. 2010. Cross-reacting antibodies enhance dengue virus infection in humans. Science 328 (5979):745-748.
Despres, P., et al. 1998. Apoptosis in the mouse central nervous system in response to infection with mouse-neurovirulent dengue viruses. J Virol 72 (1):823-829.
Espada-Murao, L. A., and K. Morita. 2011. Dengue and soluble mediators of the innate immune system. Trop Med Health 39 (4 Suppl):53-62.
Falconar, A. K. 1997. The dengue virus nonstructural-1 protein (NS1) generates antibodies to common epitopes on human blood clotting, integrin/adhesin proteins and binds to human endothelial cells: potential implications in haemorrhagic fever pathogenesis. Arch Virol 142 (5):897-916.
Falconar, A. K. 2007. Antibody responses are generated to immunodominant ELK/KLE-type motifs on the nonstructural-1 glycoprotein during live dengue virus infections in mice and humans: implications for diagnosis, pathogenesis, and vaccine design. Clin Vaccine Immunol 14 (5):493-504.
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 (9):4356-4363.
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 (5):1852-1860.
Fink, J., et al. 2006. Role of T cells, cytokines and antibody in dengue fever and dengue haemorrhagic fever. Rev Med Virol 16 (4):263-275.
Flamand, M., et al. 1999. Dengue virus type 1 nonstructural glycoprotein NS1 is secreted from mammalian cells as a soluble hexamer in a glycosylation-dependent fashion. J Virol 73 (7):6104-6110.
Fried, J. R., et al. 2010. Serotype-specific differences in the risk of dengue hemorrhagic fever: an analysis of data collected in Bangkok, Thailand from 1994 to 2006. PLoS Negl Trop Dis 4 (3):e617.
Frieman, M. B., et al. 2010. SARS-CoV pathogenesis is regulated by a STAT1 dependent but a type I, II and III interferon receptor independent mechanism. PLoS Pathog 6 (4):e1000849.
Garcia, G., et al. 2006. Antibodies from patients with dengue viral infection mediate cellular cytotoxicity. J Clin Virol 37 (1):53-57.
Green, S., et al. 1999a. Early CD69 expression on peripheral blood lymphocytes from children with dengue hemorrhagic fever. J Infect Dis 180 (5):1429-1435.
Green, S., and A. Rothman. 2006. Immunopathological mechanisms in dengue and dengue hemorrhagic fever. Curr Opin Infect Dis 19 (5):429-436.
Green, S., et al. 1999b. Elevated plasma interleukin-10 levels in acute dengue correlate with disease severity. J Med Virol 59 (3):329-334.
Gubler, D. J. 1998. Dengue and dengue hemorrhagic fever. Clin Microbiol Rev 11 (3):480-496.
Guzman, A., and R. E. Isturiz. 2010. Update on the global spread of dengue. Int J Antimicrob Agents 36 Suppl 1:S40-42.
Guzman, M. G., et al. 2010. Dengue: a continuing global threat. Nat Rev Microbiol 8 (12 Suppl):S7-16.
Halstead, S. B. 2003. Neutralization and antibody-dependent enhancement of dengue viruses. Adv Virus Res 60:421-467.
Halstead, S. B. 2007. Dengue. Lancet 370 (9599):1644-1652.
Halstead, S. B., et al. 2010. Intrinsic antibody-dependent enhancement of microbial infection in macrophages: disease regulation by immune complexes. Lancet Infect Dis 10 (10):712-722.
Heinz, F. X., and K. Stiasny. 2012. Flaviviruses and flavivirus vaccines. Vaccine 30 (29):4301-4306.
Henchal, E. A., et al. 1988. Synergistic interactions of anti-NS1 monoclonal antibodies protect passively immunized mice from lethal challenge with dengue 2 virus. J Gen Virol 69 ( Pt 8):2101-2107.
Henchal, E. A., and J. R. Putnak. 1990. The dengue viruses. Clin Microbiol Rev 3 (4):376-396.
Hoang, L. T., et al. 2010. The early whole-blood transcriptional signature of dengue virus and features associated with progression to dengue shock syndrome in Vietnamese children and young adults. J Virol 84 (24):12982-12994.
Hober, D., et al. 1993. Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 beta (IL-1 beta) in dengue-infected patients. Am J Trop Med Hyg 48 (3):324-331.
Hofer, M. J., et al. 2012. Mice Deficient in STAT1 but Not STAT2 or IRF9 Develop a Lethal CD4+ T-Cell-Mediated Disease following Infection with Lymphocytic Choriomeningitis Virus. J Virol 86 (12):6932-6946.
Huang, C. H. 2010. The protective effects provided by antibodies against chimeric dengue virus nonstructural protein 1. Master thesis of Science in Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University.
Huang, K. J., et al. 2006. The dual-specific binding of dengue virus and target cells for the antibody-dependent enhancement of dengue virus infection. J Immunol 176 (5):2825-2832.
Huang, Y. H., et al. 1997. Antibodies against dengue virus E protein peptide bind to human plasminogen and inhibit plasmin activity. Clin Exp Immunol 110 (1):35-40.
Huang, Y. H., et al. 2003. Tissue plasminogen activator induced by dengue virus infection of human endothelial cells. J Med Virol 70 (4):610-616.
Jacobs, M. G., et al. 2000. Dengue virus nonstructural protein 1 is expressed in a glycosyl-phosphatidylinositol-linked form that is capable of signal transduction. FASEB J 14 (11):1603-1610.
Joshi, R., and V. Baid. 2011. Profile of dengue patients admitted to a tertiary care hospital in Mumbai. Turk J Pediatr 53 (6):626-631.
Kalayanarooj, S. 2011. Clinical Manifestations and Management of Dengue/DHF/DSS. Trop Med Health 39 (4 Suppl):83-87.
Katze, M. G., et al. 2002. Viruses and interferon: a fight for supremacy. Nat Rev Immunol 2 (9):675-687.
Kittigul, L., et al. 2007. The differences of clinical manifestations and laboratory findings in children and adults with dengue virus infection. J Clin Virol 39 (2):76-81.
Kontny, U., et al. 1988. Gamma interferon augments Fc gamma receptor-mediated dengue virus infection of human monocytic cells. J Virol 62 (11):3928-3933.
Kou, Z., et al. 2008. Monocytes, but not T or B cells, are the principal target cells for dengue virus (DV) infection among human peripheral blood mononuclear cells. J Med Virol 80 (1):134-146.
Kouri, G. P., et al. 1989. Dengue haemorrhagic fever/dengue shock syndrome: lessons from the Cuban epidemic, 1981. Bull World Health Organ 67 (4):375-380.
Kuhn, R. J., et al. 2002. Structure of dengue virus: implications for flavivirus organization, maturation, and fusion. Cell 108 (5):717-725.
Kularatne, S. A., et al. 2005. Epidemiology, clinical features, laboratory investigations and early diagnosis of dengue fever in adults: a descriptive study in Sri Lanka. Southeast Asian J Trop Med Public Health 36 (3):686-692.
Kuno, G., and R. E. Bailey. 1994. Cytokine responses to dengue infection among Puerto Rican patients. Mem Inst Oswaldo Cruz 89 (2):179-182.
Kurane, I., et al. 1991. Activation of T lymphocytes in dengue virus infections. High levels of soluble interleukin 2 receptor, soluble CD4, soluble CD8, interleukin 2, and interferon-gamma in sera of children with dengue. J Clin Invest 88 (5):1473-1480.
Lai, C. Y., et al. 2008. Antibodies to envelope glycoprotein of dengue virus during the natural course of infection are predominantly cross-reactive and recognize epitopes containing highly conserved residues at the fusion loop of domain II. J Virol 82 (13):6631-6643.
Lee, M. S., et al. 2006a. Clinical characteristics of dengue and dengue hemorrhagic fever in a medical center of southern Taiwan during the 2002 epidemic. J Microbiol Immunol Infect 39 (2):121-129.
Lee, T. H., et al. 2012. A cross-protective mAb recognizes a novel epitope within the flavivirus NS1 protein. J Gen Virol 93 (Pt 1):20-26.
Lee, Y. R., et al. 2006b. MCP-1, a highly expressed chemokine in dengue haemorrhagic fever/dengue shock syndrome patients, may cause permeability change, possibly through reduced tight junctions of vascular endothelium cells. J Gen Virol 87 (Pt 12):3623-3630.
Lei, H. Y., et al. 2001. Immunopathogenesis of dengue virus infection. J Biomed Sci 8 (5):377-388.
Leitmeyer, K. C., et al. 1999. Dengue virus structural differences that correlate with pathogenesis. J Virol 73 (6):4738-4747.
Libraty, D. H., et al. 2002a. Differing influences of virus burden and immune activation on disease severity in secondary dengue-3 virus infections. J Infect Dis 185 (9):1213-1221.
Libraty, D. H., et al. 2001. Human dendritic cells are activated by dengue virus infection: enhancement by gamma interferon and implications for disease pathogenesis. J Virol 75 (8):3501-3508.
Libraty, D. H., et al. 2002b. High circulating levels of the dengue virus nonstructural protein NS1 early in dengue illness correlate with the development of dengue hemorrhagic fever. J Infect Dis 186 (8):1165-1168.
Lin, C. C., Y. H. Huang, P. Y. Shu, H. S. Wu, Y. S. Lin, T. M. Yeh, H. S. Liu, C. C. Liu, and H. Y. Lei. 2010. Characteristic of dengue disease in Taiwan: 2002-2007. Am J Trop Med Hyg 82 (4):731-739.
Lin, C. F., et al. 2008a. Patient and mouse antibodies against dengue virus nonstructural protein 1 cross-react with platelets and cause their dysfunction or depletion. American Journal of Infectious Diseases 4 (1):69-75.
Lin, C. F., et al. 2005. Expression of cytokine, chemokine, and adhesion molecules during endothelial cell activation induced by antibodies against dengue virus nonstructural protein 1. J Immunol 174 (1):395-403.
Lin, C. F., et al. 2001. Generation of IgM anti-platelet autoantibody in dengue patients. J Med Virol 63 (2):143-149.
Lin, C. F., et al. 2003. Antibodies from dengue patient sera cross-react with endothelial cells and induce damage. J Med Virol 69 (1):82-90.
Lin, C. F., et al. 2002. Endothelial cell apoptosis induced by antibodies against dengue virus nonstructural protein 1 via production of nitric oxide. J Immunol 169 (2):657-664.
Lin, C. F., et al. 2008b. Liver injury caused by antibodies against dengue virus nonstructural protein 1 in a murine model. Lab Invest 88 (10):1079-1089.
Lin, C. F., et al. 2006. Autoimmune pathogenesis in dengue virus infection. Viral Immunol 19 (2):127-132.
Lin, Y. S., et al. 2011. Molecular mimicry between virus and host and its implications for dengue disease pathogenesis. Exp Biol Med (Maywood) 236 (5):515-523.
Liu, I. J., et al. 2011. Molecular mimicry of human endothelial cell antigen by autoantibodies to nonstructural protein 1 of dengue virus. J Biol Chem 286 (11):9726-9736.
Mackenzie, J. M., et al. 1996. Immunolocalization of the dengue virus nonstructural glycoprotein NS1 suggests a role in viral RNA replication. Virology 220 (1):232-240.
Malasit, P. 1987. Complement and dengue haemorrhagic fever/shock syndrome. Southeast Asian J Trop Med Public Health 18 (3):316-320.
Mangada, M. M., and A. L. Rothman. 2005. Altered cytokine responses of dengue-specific CD4+ T cells to heterologous serotypes. J Immunol 175 (4):2676-2683.
Markoff, L. J., et al. 1991. Development of cross-reactive antibodies to plasminogen during the immune response to dengue virus infection. J Infect Dis 164 (2):294-301.
Martina, B. E., et al. 2009. Dengue virus pathogenesis: an integrated view. Clin Microbiol Rev 22 (4):564-581.
Masrinoul, P., et al. 2011. Highly conserved region 141-168 of the NS1 protein is a new common epitope region of dengue virus. Jpn J Infect Dis 64 (2):109-115.
Matusan, A. E., et al. 2001. Mutagenesis of the Dengue virus type 2 NS3 protein within and outside helicase motifs: effects on enzyme activity and virus replication. J Virol 75 (20):9633-9643.
Meier, K. C., et al. 2009. A mouse model for studying viscerotropic disease caused by yellow fever virus infection. PLoS Pathog 5 (10):e1000614.
Miller, J. L., et al. 2008. The mannose receptor mediates dengue virus infection of macrophages. PLoS Pathog 4 (2):e17.
Monath, T. P. 1994. Dengue: the risk to developed and developing countries. Proc Natl Acad Sci U S A 91 (7):2395-2400.
Mongkolsapaya, J., et al. 2003. Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. Nat Med 9 (7):921-927.
Mousson, L., et al. 2005. Phylogeography of Aedes (Stegomyia) aegypti (L.) and Aedes (Stegomyia) albopictus (Skuse) (Diptera: Culicidae) based on mitochondrial DNA variations. Genet Res 86 (1):1-11.
Mukhopadhyay, S., et al. 2005. A structural perspective of the flavivirus life cycle. Nat Rev Microbiol 3 (1):13-22.
Munoz-Jordan, J. L., et al. 2005. Inhibition of alpha/beta interferon signaling by the NS4B protein of flaviviruses. J Virol 79 (13):8004-8013.
Munoz-Jordan, J. L., et al. 2003. Inhibition of interferon signaling by dengue virus. Proc Natl Acad Sci U S A 100 (24):14333-14338.
Murphy, B. R., and S. S. Whitehead. 2011. Immune response to dengue virus and prospects for a vaccine. Annu Rev Immunol 29:587-619.
Netsawang, J., et al. 2010. Nuclear localization of dengue virus capsid protein is required for DAXX interaction and apoptosis. Virus Res 147 (2):275-283.
Niyomrattanakit, P., et al. 2004. Identification of residues in the dengue virus type 2 NS2B cofactor that are critical for NS3 protease activation. J Virol 78 (24):13708-13716.
Noisakran, S., et al. 2008. Association of dengue virus NS1 protein with lipid rafts. J Gen Virol 89 (Pt 10):2492-2500.
Oishi, K., et al. 2003. Correlation between increased platelet-associated IgG and thrombocytopenia in secondary dengue virus infections. J Med Virol 71 (2):259-264.
Paes, M. V., et al. 2009. Hepatic damage associated with dengue-2 virus replication in liver cells of BALB/c mice. Lab Invest 89 (10):1140-1151.
Palframan, R. T., et al. 2001. Inflammatory chemokine transport and presentation in HEV: a remote control mechanism for monocyte recruitment to lymph nodes in inflamed tissues. J Exp Med 194 (9):1361-1373.
Pang, T., et al. 2007. Of cascades and perfect storms: the immunopathogenesis of dengue haemorrhagic fever-dengue shock syndrome (DHF/DSS). Immunol Cell Biol 85 (1):43-45.
Panyasrivanit, M., et al. 2009. Co-localization of constituents of the dengue virus translation and replication machinery with amphisomes. J Gen Virol 90 (Pt 2):448-456.
Peeling, R. W., et al. 2010. Evaluation of diagnostic tests: dengue. Nat Rev Microbiol 8 (12 Suppl):S30-38.
Perry, S. T., et al. 2011. STAT2 mediates innate immunity to Dengue virus in the absence of STAT1 via the type I interferon receptor. PLoS Pathog 7 (2):e1001297.
Pinto, L. M., et al. 1999. Increased pro-inflammatory cytokines (TNF-alpha and IL-6) and anti-inflammatory compounds (sTNFRp55 and sTNFRp75) in Brazilian patients during exanthematic dengue fever. Mem Inst Oswaldo Cruz 94 (3):387-394.
Prestwood, T. R., et al. 2008. A mouse-passaged dengue virus strain with reduced affinity for heparan sulfate causes severe disease in mice by establishing increased systemic viral loads. J Virol 82 (17):8411-8421.
Raghupathy, R., et al. 1998. Elevated levels of IL-8 in dengue hemorrhagic fever. J Med Virol 56 (3):280-285.
Ramanathan, M. P., et al. 2006. Host cell killing by the West Nile Virus NS2B-NS3 proteolytic complex: NS3 alone is sufficient to recruit caspase-8-based apoptotic pathway. Virology 345 (1):56-72.
Rothman, A. L. 2004. Dengue: defining protective versus pathologic immunity. J Clin Invest 113 (7):946-951.
Rothman, A. L. 2011. Immunity to dengue virus: a tale of original antigenic sin and tropical cytokine storms. Nat Rev Immunol 11 (8):532-543.
Russell, P. K., et al. 1967. Antibody response in dengue and dengue hemorrhagic fever. Jpn J Med Sci Biol 20 Suppl:103-108.
Sabin, A. B. 1950. The dengue group of viruses and its family relationships. Bacteriol Rev 14 (3):225-232.
Saito, M., et al. 2004. Association of increased platelet-associated immunoglobulins with thrombocytopenia and the severity of disease in secondary dengue virus infections. Clin Exp Immunol 138 (2):299-303.
Schlesinger, J. J., et al. 1987. Protection of mice against dengue 2 virus encephalitis by immunization with the dengue 2 virus non-structural glycoprotein NS1. J Gen Virol 68 ( Pt 3):853-857.
Schul, W., et al. 2007. A dengue fever viremia model in mice shows reduction in viral replication and suppression of the inflammatory response after treatment with antiviral drugs. J Infect Dis 195 (5):665-674.
Shresta, S., et al. 2006. Murine model for dengue virus-induced lethal disease with increased vascular permeability. J Virol 80 (20):10208-10217.
Shresta, S., et al. 2005. Critical roles for both STAT1-dependent and STAT1-independent pathways in the control of primary dengue virus infection in mice. J Immunol 175 (6):3946-3954.
Simmons, C. P., et al. 2012. Dengue. N Engl J Med 366 (15):1423-1432.
Spain-Santana, T. A., et al. 2001. MIP-1 alpha and MIP-1 beta induction by dengue virus. J Med Virol 65 (2):324-330.
Suharti, C., et al. 2002. The role of cytokines in activation of coagulation and fibrinolysis in dengue shock syndrome. Thromb Haemost 87 (1):42-46.
Sun, D. S., et al. 2007. Antiplatelet autoantibodies elicited by dengue virus non-structural protein 1 cause thrombocytopenia and mortality in mice. J Thromb Haemost 5 (11):2291-2299.
Tung, Y. C., et al. 2008. Phylogenetic study of dengue-3 virus in Taiwan with sequence analysis of the core gene. Kaohsiung J Med Sci 24 (2):55-62.
van den Broek, M. F., et al. 1995. Immune defence in mice lacking type I and/or type II interferon receptors. Immunol Rev 148:5-18.
Vaughn, D. W., et al. 2000. Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity. J Infect Dis 181 (1):2-9.
Wan, S.W. 2011. Role of antibodies against C-terminus of dengue virus nonstructural protein 1 and autoantigen protein disulfide isomerase in dengue disease pathogenesis. PhD thesis of The Institute of Basic Medical Science, College of Medicine, National Cheng Kung University.
Wang, L., et al. 2011. DC-SIGN (CD209) Promoter -336 A/G polymorphism is associated with dengue hemorrhagic fever and correlated to DC-SIGN expression and immune augmentation. PLoS Negl Trop Dis 5 (1):e934.
Welsch, S., et al. 2009. Composition and three-dimensional architecture of the dengue virus replication and assembly sites. Cell Host Microbe 5 (4):365-375.
Welstead, G. G., et al. 2005. Measles virus replication in lymphatic cells and organs of CD150 (SLAM) transgenic mice. Proc Natl Acad Sci U S A 102 (45):16415-16420.
Westaway, E. G., et al. 1997. Ultrastructure of Kunjin virus-infected cells: colocalization of NS1 and NS3 with double-stranded RNA, and of NS2B with NS3, in virus-induced membrane structures. J Virol 71 (9):6650-6661.
Whitehead, S. S., et al. 2007. Prospects for a dengue virus vaccine. Nat Rev Microbiol 5 (7):518-528.
Whitehorn, J., and C. P. Simmons. 2011. The pathogenesis of dengue. Vaccine 29 (42):7221-7228.
Wills, B. A., et al. 2004. Size and charge characteristics of the protein leak in dengue shock syndrome. J Infect Dis 190 (4):810-818.
Winkler, G., et al. 1989. Newly synthesized dengue-2 virus nonstructural protein NS1 is a soluble protein but becomes partially hydrophobic and membrane-associated after dimerization. Virology 171 (1):302-305.
Wright, H., et al. 2005. Multiplex cytokine profiling of initial therapeutic response in patients with chronic hepatitis C virus infection. Dig Dis Sci 50 (10):1793-1803.
Wu-Hsieh, B. A., et al. 2009. Dengue hemorrhage in a mouse model. Ann N Y Acad Sci 1171 Suppl 1:E42-47.
Wu, K. L., et al. 2004. Early abdominal sonographic findings in patients with dengue fever. J Clin Ultrasound 32 (8):386-388.
Wu, S. F., et al. 2003. Evaluation of protective efficacy and immune mechanisms of using a non-structural protein NS1 in DNA vaccine against dengue 2 virus in mice. Vaccine 21 (25-26):3919-3929.
Wu, S. J., et al. 2000. Human skin Langerhans cells are targets of dengue virus infection. Nat Med 6 (7):816-820.
Yen, Y. T., et al. 2008. Enhancement by tumor necrosis factor alpha of dengue virus-induced endothelial cell production of reactive nitrogen and oxygen species is key to hemorrhage development. J Virol 82 (24):12312-12324.
Youn, S., et al. 2012. Evidence for a genetic and physical interaction between nonstructural proteins NS1 and NS4B that modulates replication of West Nile virus. J Virol 86 (13):7360-7371
Young, P. R., et al. 2000. An antigen capture enzyme-linked immunosorbent assay reveals high levels of the dengue virus protein NS1 in the sera of infected patients. J Clin Microbiol 38 (3):1053-1057.
Zompi, S., and E. Harris. 2012. Animal models of dengue virus infection. Viruses 4 (1):62-82.
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