進階搜尋


   電子論文尚未授權公開,紙本請查館藏目錄
(※如查詢不到或館藏狀況顯示「閉架不公開」,表示該本論文不在書庫,無法取用。)
系統識別號 U0026-1908201510211100
論文名稱(中文) 探討包裹在奈米複合物中修飾過的登革病毒非結構性蛋白1所引起之細胞免疫反應
論文名稱(英文) Studies on the cellular immune responses induced by chimeric dengue virus nonstructural protein 1-encapsulated nanocomplexes
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 103
學期 2
出版年 104
研究生(中文) 利宗霖
研究生(英文) Chung-Lin Li
學號 S46021016
學位類別 碩士
語文別 英文
論文頁數 67頁
口試委員 指導教授-林以行
口試委員-林秋烽
口試委員-張志鵬
口試委員-陳毓宏
口試委員-羅伯安德森
中文關鍵字 登革病毒  非結構性蛋白1  高分子奈米複合物: 細胞免疫反應 
英文關鍵字 dengue virus  nonstructural protein 1  polymer-based nanocomplexes  cellular immune responses 
學科別分類
中文摘要 根據WHO報導,全世界超過25億人口目前在登革病毒(dengue virus; DENV)感染的風險之下,每年大約有三億九千萬人受到登革病毒感染。然而目前並沒有抗病毒藥物或是疫苗可供使用。我們先前的研究發現,登革病毒非結構性蛋白1 (NS1)之C端序列與自體抗原具有分子相似性,造成由抗登革病毒NS1之抗體所引起的血管內皮細胞凋亡以及血小板凝集機制失能。因此,我們將NS1之N端序列(胺基酸1-270)保留,C端序列(胺基酸271-352)與日本腦炎病毒NS1之C端序列做置換,產生了名為DJ NS1之嵌合蛋白質。實驗室的研究指出,主動免疫小鼠包裹DJ NS1的高分子奈米複合物不只可以引起較好的抗DJ NS1之抗體,也可以有效的降低由登革病毒所引起小鼠出血時間延長現象。包裹DJ NS1的高分子奈米複合物也可以使小鼠產生較久的抗體反應且提供長期保護。除了體液免疫反應,我們也想知道包裹DJ NS1的高分子奈米複合物是否可以引起細胞免疫反應。相較於鋁鹽,利用高分子奈米複合物作為佐劑,在in vitro或in vivo可以引起較好的樹突細胞(dendritic cells; DCs)活化,且使樹突細胞攝取較多的抗原。在老鼠實驗中,當再一次遇到相同抗原,小鼠主動免疫包裹DJ NS1的高分子奈米複合物可以引起較好的淋巴細胞的增生以及T細胞的活化。另外,藉由細胞激素的偵測,包裹DJ NS1的高分子奈米複合物可以同時引起Th1及Th2的反應。更進一步,主動免疫包裹DJ NS1的高分子奈米複合物可以引起有毒殺性的NS1-specific CD8+ T 細胞,然而NS1-specific CD8+ T細胞對於降低登革病毒所引起小鼠出血時間延長現象影響較小。除此之外,包裹DJ NS1的高分子奈米複合物可以引起較持久的樹突細胞以及T細胞的活化。綜合以上,包裹DJ NS1的高分子奈米複合物可以同時引起體液及細胞免疫反應,提供了具潛力的疫苗來對抗登革病毒。
英文摘要 Based on WHO report, over 2.5 billion people are now at risk from dengue virus (DENV) and there are approximately 390 million DENV infections worldwide every year. However, there is still no approved antiviral treatment or vaccine available. Our previous studies showed that the C-terminal region of DENV nonstructural protein 1 (NS1) is responsible for molecular mimicry that causes anti-DENV NS1 antibody-mediated endothelial cell apoptosis and platelet dysfunction. Therefore, we have generated a chimeric NS1 protein, which consists of N-terminal region of DENV NS1 (amino acids 1-270) and C-terminal region of Japanese encephalitis virus NS1 (amino acids 271-352), called DJ NS1 as a potential candidate for DENV vaccine. Our previous studies showed that active immunization with DJ NS1-encapsulated nanocomplexes not only induced higher anti-DJ NS1 antibody titers than DJ NS1 plus alum, but also significantly decreased the DENV-induced prolonged bleeding time in the mouse model. DJ NS1-encapsulated nanocomplexes induced longer antibody persistence and provided long-term protection. Besides humoral immune responses, in the present study we further investigated whether DJ NS1-encapsulated nanocomplexes can also induce cellular immune responses. Polymer-based nanocomplexes as adjuvant induce dendritic cell (DC) activation both in vitro and in vivo and better antigen uptake than alum in vitro. In the mouse model, mice immunized with DJ NS1-encapsulated nanocomplexes induced better lymphocyte proliferation and T cell activation than alum in response to DJ NS1 antigen. In addition, DJ NS1-encapsulated nanocomplexes induced both Th1/Th2 responses as determined by cytokine production. Moreover, mice immunized with DJ NS1-encapsulated nanocomplexes induced NS1-specific CD8+ T cell cytotoxicity, while NS1-specific CD8+ T cells caused only a minor effect on DENV-induced prolonged bleeding time. Furthermore, DJ NS1-encapsulated nanocomplexes induced DC and T cell long-lasting activation better than alum. Taken together, DJ NS1-encapsulated nanocomplexes induce both humoral and cellular immune responses which provide a potential vaccine candidate against DENV.
論文目次 中文摘要 I
Abstract II
Acknowledgement IV
Contents V
Figure List VIII
Abbreviations X
Introduction 1
Characteristics of dengue virus 1
Epidemiology of dengue virus infection 4
Clinical symptoms of dengue disease 4
The pathogenesis of dengue virus infection 5
Immune responses of dengue virus 7
Vaccine adjuvants 8
Dengue vaccine development 11
Objective and Specific Aims 13
1. To determine the antibody responses induced by DJ NS1-encapsulated nanocomplexes. 13
2. To determine whether polymer-based nanocomplexes as adjuvant promote antigen uptake and antigen-presenting cell activation. 14
3. To determine lymphocyte proliferation, cytokine profile, and T cell activation induced by DJ NS1-encapsulated nanocomplexes. 14
4. To investigate CD8+ T cell cytotoxicity induced by DJ NS1-encapulated nanocomplexes. 14
5. To investigate the long-lasting activation provided by DJ NS1-encapsulated nanocomplexes. 15
Materials and Methods 16
A. Materials 16
A-1 Mice 16
A-2 Cell lines 16
A-3 Viruses 16
A-4 Preparation of recombinant proteins 17
A-5 Preparation of DJ NS1-encapsulated polymer-based nanocomplexes 17
A-6 Drugs and reagents 18
A-7 Antibodies 21
A-8 Kits 21
A-9 Consumables 22
A-10 Instruments 23
B. Methods 26
B-1 Cell cultures 26
B-2 Virus culture 26
B-3 Plaque assay 26
B-4 Antibody titer determination 27
B-5 Western blotting 27
B-6 Mouse tail bleeding time 27
B-7 Uptake of DJ NS1-encapsulated nanocomplexes by DC2.4 cells 28
B-8 Lymphocyte proliferation assay 28
B-9 Analysis for dendritic cell activation 28
B-10 Analysis for CD4+ and CD8+ T cell activation 29
B-11 Active immunization mouse model 29
B-12 Lactate dehydrogenase-based cytotoxic assay 29
B-13 Detection of cytokines in culture supernatants 30
B-14 Statistics 31
Results 32
1. To determine the antibody responses induced by DJ NS1-encapsulated nanocomplexes. 32
1.1 Preparation of the DJ NS1 protein. 32
1.2 Active immunization with DJ NS1-encapsulated nanocomplexes induces better antibody response than DJ NS1 plus alum. 32
2. To determine whether nanocomplexes as adjuvant promote antigen uptake and antigen-presenting cell activation. 33
2.1 Uptake of DJ NS1 with different adjuvants by DC2.4 cells. 33
2.2 DJ NS1-encapsulated nanocomplexes up-regulate the expression of MHC class I, II, and costimulatory receptors in DC2.4 cells. 33
2.3 DJ NS1-encapsulated nanocomplexes up-regulate mouse lymph node dendritic cell costimulatory receptors ex vivo. 34
3. To determine lymphocyte proliferation, cytokine production and T cell activation induced by DJ NS1-encapsulated nanocomplexes. 34
3.1 Nanocomplexes induce better lymphocyte proliferation than alum in response to DJ NS1 antigen. 35
3.2 DJ NS1-encapsulated nanocomplexes induce both Th1 and Th2 cytokine production. 35
3.3 DJ NS1-encapsulated nanocomplexes induce both CD4+ and CD8+ T cell activation in response to DJ NS1 antigen. 36
4. To investigate CD8+ T cell cytotoxicity induced by DJ NS1-encapulated nanocomplexes. 37
4.1 Immunization with DJ NS1-encapsulated nanocomplexes induce cytotoxic T lymphocyte (CTL) responses. 37
4.2 Immunization with DJ NS1-encapsulated nanocomplexes induce NS1-specific CTL responses. 37
4.3 CD8+ T cells induced by DJ NS1-encapsulated nanocomplexes cause minor effect in DENV-induced prolonged bleeding time. 38
5. To investigate the long-lasting activation provided by DJ NS1-encapsulated nanocomplexes. 39
Discussion 41
References 46
Figures 54
參考文獻 Akira, S., Takeda, K. and Kaisho, T. (2001). Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2, 675-680.
Amorim, J.H., Alves, R.P., Boscardin, S.B. and Ferreira, L.C. (2014). The dengue virus non-structural 1 protein: risks and benefits. Virus Res 181, 53-60.
Anderson, R., Wang, S., Osiowy, C. and Issekutz, A.C. (1997). Activation of endothelial cells via antibody-enhanced dengue virus infection of peripheral blood monocytes. J Virol 71, 4226-4232.
Ashour, J., Laurent-Rolle, M., Shi, P.Y. and Garcia-Sastre, A. (2009). NS5 of dengue virus mediates STAT2 binding and degradation. J Virol 83, 5408-5418.
Avirutnan, P., Punyadee, N., Noisakran, S., Komoltri, C., Thiemmeca, S., Auethavornanan, K., 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, 1078-1088.
Badiee, A., Heravi Shargh, V., Khamesipour, A. and Jaafari, M.R. (2013). Micro/nanoparticle adjuvants for antileishmanial vaccines: present and future trends. Vaccine 31, 735-749.
Bhatt, S., Gething, P.W., Brady, O.J., Messina, J.P., Farlow, A.W., Moyes, C.L., et al. (2013). The global distribution and burden of dengue. Nature 496, 504-507.
Capeding, M.R., Tran, N.H., Hadinegoro, S.R., Ismail, H.I., Chotpitayasunondh, T., Chua, M.N., et al. (2014). Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. Lancet 384, 1358-1365.
Chang, S.F., Huang, J.H. and Shu, P.Y. (2012). Characteristics of dengue epidemics in Taiwan. J Formos Med Assoc 111, 297-299.
Chen, C.Y. (2014). Studies on the protective effect of chimeric dengue virus nonstructural protein 1 with polymeric nanocomplex-based adjuvant in the mouse model. Master thesis of Science in Department of Microbiology and Immunology, College of Medicine, National Chen Kung University.
Chen, M.C., Lin, C.F., Lei, H.Y., Lin, S.C., Liu, H.S., Yeh, T.M., 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, 1797-1803.
Chen, Y., Maguire, T., Hileman, R.E., Fromm, J.R., Esko, J.D., Linhardt, R.J. and Marks, R.M. (1997). Dengue virus infectivity depends on envelope protein binding to target cell heparan sulfate. Nat Med 3, 866-871.
Chokephaibulkit, K. and Perng, G.C. (2013). Challenges for the formulation of a universal vaccine against dengue. Exp Biol Med (Maywood) 238, 566-578.
Dewi, B.E., Takasaki, T. and Kurane, I. (2004). In vitro assessment of human endothelial cell permeability: effects of inflammatory cytokines and dengue virus infection. J Virol Methods 121, 171-180.
Duangchinda, T., Dejnirattisai, W., Vasanawathana, S., Limpitikul, W., Tangthawornchaikul, N., Malasit, P., et al. (2010). Immunodominant T-cell responses to dengue virus NS3 are associated with DHF. Proc Natl Acad Sci U S A 107, 16922-16927.
Eidsmo, L., Allan, R., Caminschi, I., van Rooijen, N., Heath, W.R. and Carbone, F.R. (2009). Differential migration of epidermal and dermal dendritic cells during skin infection. J Immunol 182, 3165-3172.
Falgout, B., Bray, M., Schlesinger, J.J. and Lai, C.J. (1990). Immunization of mice with recombinant vaccinia virus expressing authentic dengue virus nonstructural protein NS1 protects against lethal dengue virus encephalitis. J Virol 64, 4356-4363.
Flamand, M., Megret, F., Mathieu, M., Lepault, J., Rey, F.A. and Deubel, V. (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, 6104-6110.
Fromen, C.A., Robbins, G.R., Shen, T.W., Kai, M.P., Ting, J.P. and DeSimone, J.M. (2015). Controlled analysis of nanoparticle charge on mucosal and systemic antibody responses following pulmonary immunization. Proc Natl Acad Sci U S A 112, 488-493.
Gao, G., Wang, Q., Dai, Z., Calcedo, R., Sun, X., Li, G. and Wilson, J.M. (2008). Adenovirus-based vaccines generate cytotoxic T lymphocytes to epitopes of NS1 from dengue virus that are present in all major serotypes. Hum Gene Ther 19, 927-936.
Gil, L., Lopez, C., Blanco, A., Lazo, L., Martin, J., Valdes, I., et al. (2009). The cellular immune response plays an important role in protecting against dengue virus in the mouse encephalitis model. Viral Immunol 22, 23-30.
Gregory, A.E., Titball, R. and Williamson, D. (2013). Vaccine delivery using nanoparticles. Front Cell Infect Microbiol 3, 13.
Grenha, A., Seijo, B. and Remunan-Lopez, C. (2005). Microencapsulated chitosan nanoparticles for lung protein delivery. Eur J Pharm Sci 25, 427-437.
Gubler, D.J. (1998). Dengue and dengue hemorrhagic fever. Clin Microbiol Rev 11, 480-496.
Hadinegoro, S.R. (2012). The revised WHO dengue case classification: does the system need to be modified? Paediatr Int Child Health 32 Suppl 1, 33-38.
Halstead, S.B. (1988). Pathogenesis of dengue: challenges to molecular biology. Science 239, 476-481.
Halstead, S.B. (2007). Dengue. Lancet 370, 1644-1652.
Halstead, S.B., Mahalingam, S., Marovich, M.A., Ubol, S. and Mosser, D.M. (2010). Intrinsic antibody-dependent enhancement of microbial infection in macrophages: disease regulation by immune complexes. Lancet Infect Dis 10, 712-722.
Halstead, S.B. and Simasthien, P. (1970). Observations related to the pathogenesis of dengue hemorrhagic fever. II. Antigenic and biologic properties of dengue viruses and their association with disease response in the host. Yale J Biol Med 42, 276-292.
Henchal, E.A. and Putnak, J.R. (1990). The dengue viruses. Clin Microbiol Rev 3, 376-396.
Henriques, H.R., Rampazo, E.V., Goncalves, A.J., Vicentin, E.C., Amorim, J.H., Panatieri, R.H., et al. (2013). Targeting the non-structural protein 1 from dengue virus to a dendritic cell population confers protective immunity to lethal virus challenge. PLoS Negl Trop Dis 7, e2330.
Hober, D., Delannoy, A.S., Benyoucef, S., De Groote, D. and Wattre, P. (1996). High levels of sTNFR p75 and TNF alpha in dengue-infected patients. Microbiol Immunol 40, 569-573.
Hogenesch, H. (2012). Mechanism of immunopotentiation and safety of aluminum adjuvants. Front Immunol 3, 406.
Hsieh, C.S., Macatonia, S.E., Tripp, C.S., Wolf, S.F., O'Garra, A. and Murphy, K.M. (1993). Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 260, 547-549.
Jacobs, M.G., Robinson, P.J., Bletchly, C., Mackenzie, J.M. and Young, P.R. (2000). Dengue virus nonstructural protein 1 is expressed in a glycosyl-phosphatidylinositol-linked form that is capable of signal transduction. FASEB J 14, 1603-1610.
Jordan, M.B., Mills, D.M., Kappler, J., Marrack, P. and Cambier, J.C. (2004). Promotion of B cell immune responses via an alum-induced myeloid cell population. Science 304, 1808-1810.
Kanchan, V. and Panda, A.K. (2007). Interactions of antigen-loaded polylactide particles with macrophages and their correlation with the immune response. Biomaterials 28, 5344-5357.
Klenerman, P. and Zinkernagel, R.M. (1998). Original antigenic sin impairs cytotoxic T lymphocyte responses to viruses bearing variant epitopes. Nature 394, 482-485.
Kurane, I. (2010). The Effect of Global Warming on Infectious Diseases. Osong Public Health Res Perspect 1, 4-9.
Lai, C.Y., Tsai, W.Y., Lin, S.R., Kao, C.L., Hu, H.P., King, C.C., 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, 6631-6643.
Lee, S. and Nguyen, M.T. (2015). Recent Advances of Vaccine Adjuvants for Infectious Diseases. Immune Netw 15, 51-57.
Leitmeyer, K.C., Vaughn, D.W., Watts, D.M., Salas, R., Villalobos, I., de, C., et al. (1999). Dengue Virus Structural Differences That Correlate with Pathogenesis. J Virol 73, 4738-4747.
Lin, C.F., Lei, H.Y., Liu, C.C., Liu, H.S., Yeh, T.M., Wang, S.T., et al. (2001). Generation of IgM anti-platelet autoantibody in dengue patients. J Med Virol 63, 143-149.
Lin, C.F., Lei, H.Y., Shiau, A.L., Liu, C.C., Liu, H.S., Yeh, T.M., et al. (2003). Antibodies from dengue patient sera cross-react with endothelial cells and induce damage. J Med Virol 69, 82-90.
Lin, C.F., Lei, H.Y., Shiau, A.L., Liu, H.S., Yeh, T.M., Chen, S.H., et al. (2002). Endothelial cell apoptosis induced by antibodies against dengue virus nonstructural protein 1 via production of nitric oxide. J Immunol 169, 657-664.
Lin, C.F., Wan, S.W., Cheng, H.J., Lei, H.Y. and Lin, Y.S. (2006). Autoimmune pathogenesis in dengue virus infection. Viral Immunol 19, 127-132.
Lin, Y.S., Yeh, T.M., Lin, C.F., Wan, S.W., Chuang, Y.C., Hsu, T.K., et al. (2011). Molecular mimicry between virus and host and its implications for dengue disease pathogenesis. Exp Biol Med (Maywood) 236, 515-523.
Lindblad, E.B. (2004). Aluminium adjuvants--in retrospect and prospect. Vaccine 22, 3658-3668.
Liu, I.J., Chiu, C.Y., Chen, Y.C. and Wu, H.C. (2011). Molecular mimicry of human endothelial cell antigen by autoantibodies to nonstructural protein 1 of dengue virus. J Biol Chem 286, 9726-9736.
Liu, W.J., Chen, H.B. and Khromykh, A.A. (2003). Molecular and functional analyses of Kunjin virus infectious cDNA clones demonstrate the essential roles for NS2A in virus assembly and for a nonconservative residue in NS3 in RNA replication. J Virol 77, 7804-7813.
Lobigs, M. (1993). Flavivirus premembrane protein cleavage and spike heterodimer secretion require the function of the viral proteinase NS3. Proc Natl Acad Sci U S A 90, 6218-6222.
Mackenzie, J.M., Jones, M.K. and Young, P.R. (1996). Immunolocalization of the dengue virus nonstructural glycoprotein NS1 suggests a role in viral RNA replication. Virology 220, 232-240.
Mackenzie, J.M., Khromykh, A.A., Jones, M.K. and Westaway, E.G. (1998). Subcellular localization and some biochemical properties of the flavivirus Kunjin nonstructural proteins NS2A and NS4A. Virology 245, 203-215.
Markoff, L., Falgout, B. and Chang, A. (1997). A conserved internal hydrophobic domain mediates the stable membrane integration of the dengue virus capsid protein. Virology 233, 105-117.
Martina, B.E., Koraka, P. and Osterhaus, A.D. (2009). Dengue virus pathogenesis: an integrated view. Clin Microbiol Rev 22, 564-581.
McLean, J.E., Wudzinska, A., Datan, E., Quaglino, D. and Zakeri, Z. (2011). Flavivirus NS4A-induced autophagy protects cells against death and enhances virus replication. J Biol Chem 286, 22147-22159.
Mohr, E., Cunningham, A.F., Toellner, K.M., Bobat, S., Coughlan, R.E., Bird, R.A., et al. (2010). IFN-{gamma} produced by CD8 T cells induces T-bet-dependent and -independent class switching in B cells in responses to alum-precipitated protein vaccine. Proc Natl Acad Sci U S A 107, 17292-17297.
Mukai, Y., Yoshinaga, T., Yoshikawa, M., Matsuo, K., Yoshikawa, T., Matsuo, K., et al. (2011). Induction of endoplasmic reticulum-endosome fusion for antigen cross-presentation induced by poly (gamma-glutamic acid) nanoparticles. J Immunol 187, 6249-6255.
Mukhopadhyay, S., Kuhn, R.J. and Rossmann, M.G. (2005). A structural perspective of the flavivirus life cycle. Nat Rev Microbiol 3, 13-22.
Munoz-Jordan, J.L., Laurent-Rolle, M., Ashour, J., Martinez-Sobrido, L., Ashok, M., Lipkin, W.I. and Garcia-Sastre, A. (2005). Inhibition of alpha/beta interferon signaling by the NS4B protein of flaviviruses. J Virol 79, 8004-8013.
Noisakran, S., Dechtawewat, T., Avirutnan, P., Kinoshita, T., Siripanyaphinyo, U., Puttikhunt, C., et al. (2008). Association of dengue virus NS1 protein with lipid rafts. J Gen Virol 89, 2492-2500.
Pang, T., Cardosa, M.J. and Guzman, M.G. (2007). Of cascades and perfect storms: the immunopathogenesis of dengue haemorrhagic fever-dengue shock syndrome (DHF/DSS). Immunol Cell Biol 85, 43-45.
Perera, R. and Kuhn, R.J. (2008). Structural Proteomics of Dengue Virus. Curr Opin Microbiol 11, 369-377.
Prestwood, T.R., Prigozhin, D.M., Sharar, K.L., Zellweger, R.M. and Shresta, S. (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, 8411-8421.
Ramanathan, M.P., Chambers, J.A., Pankhong, P., Chattergoon, M., Attatippaholkun, W., Dang, K., 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, 56-72.
Ramon, G. (1924). Sur la toxine et sur I’anatoxine diphtheriques. Ann. Inst. Pasteur 38, 1-10.
Ranjit, S. and Kissoon, N. (2011). Dengue hemorrhagic fever and shock syndromes. Pediatr Crit Care Med 12, 90-100.
Remakus, S. and Sigal, L.J. (2013). Memory CD8(+) T cell protection. Adv Exp Med Biol 785, 77-86.
Rodenhuis-Zybert, I., Wilschut, J. and Smit, J. (2010). Dengue virus life cycle: viral and host factors modulating infectivity. Cell. Mol. Life Sci. 67, 2773-2786.
Rothman, A.L. (2011). Immunity to dengue virus: a tale of original antigenic sin and tropical cytokine storms. Nat Rev Immunol 11, 532-543.
Sabchareon, A., Wallace, D., Sirivichayakul, C., Limkittikul, K., Chanthavanich, P., Suvannadabba, S., et al. (2012). Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial. Lancet 380, 1559-1567.
Sant, A.J. and McMichael, A. (2012). Revealing the role of CD4(+) T cells in viral immunity. J Exp Med 209, 1391-1395.
Saraiva, M. and O'Garra, A. (2010). The regulation of IL-10 production by immune cells. Nat Rev Immunol 10, 170-181.
Selin, L.K., Cornberg, M., Brehm, M.A., Kim, S.-K., Calcagno, C., Ghersi, D., et al. (2004). CD8 memory T cells: cross-reactivity and heterologous immunity. Semin Immunol 16, 335-347.
Shen, H., Ackerman, A.L., Cody, V., Giodini, A., Hinson, E.R., Cresswell, P., et al. (2006). Enhanced and prolonged cross-presentation following endosomal escape of exogenous antigens encapsulated in biodegradable nanoparticles. Immunology 117, 78-88.
Singh, M. and O'Hagan, D. (1999). Advances in vaccine adjuvants. Nat Biotechnol 17, 1075-1081.
Suharti, C., van Gorp, E.C., Setiati, T.E., Dolmans, W.M., Djokomoeljanto, R.J., Hack, C.E., et al. (2002). The role of cytokines in activation of coagulation and fibrinolysis in dengue shock syndrome. Thromb Haemost 87, 42-46.
Sun, D.S., King, C.C., Huang, H.S., Shih, Y.L., Lee, C.C., Tsai, W.J., et al. (2007). Antiplatelet autoantibodies elicited by dengue virus non-structural protein 1 cause thrombocytopenia and mortality in mice. J Thromb Haemost 5, 2291-2299.
Tavare, R., McCracken, M.N., Zettlitz, K.A., Knowles, S.M., Salazar, F.B., Olafsen, T., et al. (2014). Engineered antibody fragments for immuno-PET imaging of endogenous CD8+ T cells in vivo. Proc Natl Acad Sci U S A 111, 1108-1113.
Teo, C.S. and Chu, J.J. (2014). Cellular vimentin regulates construction of dengue virus replication complexes through interaction with NS4A protein. J Virol 88, 1897-1913.
Tian, J., Zeng, G., Pang, X., Liang, M., Zhou, J., Fang, D., et al. (2012). Identification and immunogenicity of two new HLA-A*0201-restricted CD8+ T-cell epitopes on dengue NS1 protein. Int Immunol 24, 207-218.
Torchilin, V.P. (2006). Multifunctional nanocarriers. Adv Drug Deliv Rev 58, 1532-1555.
Treuel, L., Jiang, X. and Nienhaus, G.U. (2013). New views on cellular uptake and trafficking of manufactured nanoparticles. J. R. Soc. Interface 10, 20120939.
Tung, Y.C., Lin, K.H., Chang, K., Ke, L.Y., Ke, G.M., Lu, P.L., et al. (2008). Phylogenetic study of dengue-3 virus in Taiwan with sequence analysis of the core gene. Kaohsiung J Med Sci 24, 55-62.
Umareddy, I., Chao, A., Sampath, A., Gu, F. and Vasudevan, S.G. (2006). Dengue virus NS4B interacts with NS3 and dissociates it from single-stranded RNA. J Gen Virol 87, 2605-2614.
Uto, T., Akagi, T., Toyama, M., Nishi, Y., Shima, F., Akashi, M. and Baba, M. (2011a). Comparative activity of biodegradable nanoparticles with aluminum adjuvants: antigen uptake by dendritic cells and induction of immune response in mice. Immunol Lett 140, 36-43.
Uto, T., Akagi, T., Yoshinaga, K., Toyama, M., Akashi, M. and Baba, M. (2011b). The induction of innate and adaptive immunity by biodegradable poly(gamma-glutamic acid) nanoparticles via a TLR4 and MyD88 signaling pathway. Biomaterials 32, 5206-5212.
Vogt, M.R., Moesker, B., Goudsmit, J., Jongeneelen, M., Austin, S.K., Oliphant, T., et al. (2009). Human monoclonal antibodies against West Nile virus induced by natural infection neutralize at a postattachment step. J Virol 83, 6494-6507.
Wan, S.W., Lin, C.F., Wang, S., Chen, Y.H., Yeh, T.M., Liu, H.S., et al. (2013a). Current progress in dengue vaccines. J Biomed Sci 20, 37.
Wan, S.W., Lin, C.F., Yeh, T.M., Liu, C.C., Liu, H.S., Wang, S., et al. (2013b). Autoimmunity in dengue pathogenesis. J Formos Med Assoc 112, 3-11.
Wan, S.W., Lu, Y.T., Huang, C.H., Lin, C.F., Anderson, R., Liu, H.S., et al. (2014). Protection against dengue virus infection in mice by administration of antibodies against modified nonstructural protein 1. PloS one 9, e92495.
Weiskopf, D., Angelo, M.A., de Azeredo, E.L., Sidney, J., Greenbaum, J.A., Fernando, A.N., et al. (2013). Comprehensive analysis of dengue virus-specific responses supports an HLA-linked protective role for CD8+ T cells. Proc Natl Acad Sci U S A 110, E2046-2053.
Weiskopf, D. and Sette, A. (2014). T-Cell Immunity to Infection with Dengue Virus in Humans. Front Immunol 5, 93.
Whitehead, S.S., Blaney, J.E., Durbin, A.P. and Murphy, B.R. (2007). Prospects for a dengue virus vaccine. Nat Rev Microbiol 5, 518-528.
Whitehorn, J. and Farrar, J. (2010). Dengue. Br Med Bull 95, 161-173.
Wu-Hsieh, B.A., Yen, Y.T. and Chen, H.C. (2009). Dengue hemorrhage in a mouse model. Ann N Y Acad Sci 1171 Suppl 1, E42-47.
Zaharoff, D.A., Rogers, C.J., Hance, K.W., Schlom, J. and Greiner, J.W. (2007). Chitosan solution enhances both humoral and cell-mediated immune responses to subcutaneous vaccination. Vaccine 25, 2085-2094.
Zellweger, R.M., Miller, R., Eddy, W.E., White, L.J., Johnston, R.E. and Shresta, S. (2013). Role of humoral versus cellular responses induced by a protective dengue vaccine candidate. PLoS Pathog 9, e1003723.
Zinkernagel, R.M. and Doherty, P.C. (1975). H-2 compatability requirement for T-cell-mediated lysis of target cells infected with lymphocytic choriomeningitis virus. Different cytotoxic T-cell specificities are associated with structures coded for in H-2K or H-2D. J Exp Med 141, 1427-1436.
Zompi, S., Santich, B.H., Beatty, P.R. and Harris, E. (2012). Protection from secondary dengue virus infection in a mouse model reveals the role of serotype cross-reactive B and T cells. J Immunol 188, 404-416.
Zou, J., Xie, X., Wang, Q.Y., Dong, H., Lee, M.Y., Kang, C., et al. (2015). Characterization of dengue virus NS4A and NS4B protein interaction. J Virol 89, 3455-3470.
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2020-08-31起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw