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 U0026-2408201704044400
論文名稱(中文) 登革病毒非結構蛋白 1 引發血小板活化與凋亡
論文名稱(英文) Dengue virus nonstructural protein 1 induces platelet activation and apoptosis
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 105
學期 2
出版年 106
研究生(中文) 吳瑋爵
研究生(英文) Wei-Chueh Wu
學號 T36041049
學位類別 碩士
語文別 英文
論文頁數 69頁
口試委員 指導教授-葉才明
口試委員-林以行
口試委員-彭貴春
口試委員-劉清泉
中文關鍵字 登革病毒  非結構性蛋白1  血小板  血小板數量低下 
英文關鍵字 dengue virus  nonstructural protein 1  platelet  thrombocytopenia 
學科別分類
中文摘要 登革病毒 (Dengue virus; DENV) 是一種藉由蚊子傳播的黃熱屬病毒,且全球平均每年約有3.9億的人口會被登革病毒感染。DENV除了能夠造成大家所熟知的典型登革熱 (dengue fever) 外,也可能引起嚴重甚至會致死的登革出血熱 (dengue hemorrhagic fever, DHF) 或登革休克症候群 (dengue shock syndrome, DSS)。患有DHF或DSS的病人常會出現一些典型的病徵包括異常出血及血小板數量低下。登革病毒非結構性蛋白1 (nonstructural protein 1, NS1) 是一個在登革感染過程中會出現在患者血液中的蛋白且在先前有不少篇研究證實DENV NS1能夠造成血管滲漏。然而,是否DENV NS1也會造成血小板數量低下則仍待釐清。先前的研究發現在登革病人血液中的血小板有增加活化與凋亡的現象,並且與病人血小板數量的減少呈現正相關。因此我們認為很有可能血液中的DENV NS1蛋白會引起血小板的活化與凋亡並進而造成血小板數量低下。為了驗證這個假說,我們使用由果蠅所產的重組DENV NS1蛋白來與正常人的血小板進行反應,並檢查是否會造成血小板的活化與凋亡。首先,我們發現DENV NS1可以黏附到血小板的表面藉由與血小板表面的類鐸受體 4反應。接著,我們發現DENV NS1能夠使血小板的活化指標P-selectin大量表現,而這樣的現象則可以被針對NS1的單株抗體所抑制。此外,血小板在加入低劑量的血小板刺激劑ADP前如果有接受DENV NS1的刺激,血小板的凝集能力也會有增強的現象。同時,我們也發現DENV NS1能夠造成血小板的凋亡包括引發一些細胞凋亡的現象:phosphatidylserine的外翻、caspase 9跟3的活化及血小板粒線體中的活性氧化物質 (Reactive oxygen species, ROS) 製造增加;而且DENV NS1可以刺激血小板分泌巨噬細胞移動抑制因子(macrophage migration inhibitory factor, MIF),MIF已知與血管通透性增加有關。最後我們更發現DENV NS1能夠增加血小板對白血球的黏附,尤其和嗜中性球。總括以上的結果,我們發現DENV NS1能夠引發血小板活化與凋亡,並且可能對於登革病毒感染所造成的血小板數量低下扮演一定的重要角色。
英文摘要 Dengue virus (DENV), a mosquito-borne flavivirus, is responsible for ~390 million infections annually, and leads to dengue fever or potentially lethal dengue hemorrhagic fever (DHF) or shock syndrome (DSS). DHF/DSS patients often show symptoms such as vascular leakage and thrombocytopenia. During dengue infection, DENV nonstructural protein 1 (NS1) can be secreted into blood and causes vascular leakage. However, whether DENV NS1 is involved in the pathogenesis of thrombocytopenia remains unclear. In previous study, it has been shown that low platelet counts coexist with high platelet activation and apoptosis in dengue patients. In this study, we hypothesized that DENV NS1 may play a critical role to induce platelet activation and apoptosis, which may contribute to thrombocytopenia during dengue infection. To test this hypothesis, freshly-isolated platelets from healthy donors were treated with DENV recombinant NS1 from drosophila and were evaluated for markers of activation and apoptosis. First, our result showed that DENV NS1 can bind to platelets via interacting with Toll-like receptor 4 (TLR4) on platelet surface. Then, we found that the platelet activation marker, P-selectin, was highly expressed in DENV NS1-stimulated platelets and the increased expression could be inhibited by anti-NS1 monoclonal antibody. Furthermore, DENV NS1 pretreatment enhanced platelets aggregation induced by suboptimal dose of ADP stimulation. Moreover, DENV NS1-stimulated platelets exhibited signs of apoptosis such as increased surface phosphatidylserine exposure, mitochondrial ROS production and activation of caspase-9 and -3. Interestingly, the secretion of macrophage migration inhibitory factor (MIF), a cytokine which may increases vascular permeability, was also increased in DENV NS1-stimulated platelets. Finally, we found that DENV NS1 can also increase adhesion of platelets to leukocytes, particular neutrophils. Taken together, our results suggest that DENV NS1 could directly induce platelet activation and apoptosis, which may contribute to the pathogenesis of thrombocytopenia during dengue infection.
論文目次 中文摘要 I
Abstract III
Acknowledgement V
Table of Contents VI
List of Figures IX
Abbreviations Index X
1. Introduction 1
1.1. Dengue virus 1
1.1.1. Dengue virus infection: Epidemiology 1
1.1.2. Characteristics of dengue virus 2
1.1.3. DENV nonstructural protein 1 3
1.1.4. Clinical symptoms and diagnostic methods of DENV infection 5
1.2. Thrombocytopenia in dengue 6
1.2.1. Characteristics of platelet 7
1.2.2. The possible mechanisms of thrombocytopenia in dengue 9
2. Objective and Specific Aims 12
1. To determine whether DENV NS1 can induce platelet activation. 12
2. To determine whether DENV NS1 can induce platelet apoptosis. 13
3. To determine whether DENV NS1 can increase adhesion of platelets to leukocyte 13
4. To determine whether DENV NS1-stimulated platelet may increase endothelium permeability 13
3. Materials and Methods 14
3.1. Materials 14
3.1.1. Proteins 14
3.1.2. Reagents 14
3.1.3. Antibodies 16
3.1.4. Consumables 17
3.1.5. Instruments 18
3.2. Methods 19
3.2.1. Isolation of peripheral blood platelets and leukocytes 19
3.2.2. In vitro platelet stimulation 20
3.2.3. Flow cytometric analysis for DENV NS1 binding 20
3.2.4. Flow cytometric analysis for P-selectin expression 21
3.2.5. Flow cytometric analysis for phosphatidylserine exposure 21
3.2.6. Flow cytometric analysis for mitochondrial-derived reactive oxygen species (ROS) production 21
3.2.7. Platelet aggregation test 22
3.2.8. Indirect immunofluorescence assay 22
3.2.9. SDS-PAGE 22
3.2.10. Western blot 23
3.2.11. ELISA 23
3.2.12. Liu’s stain 23
3.2.13. Statistical analysis 24
4. Results 25
4.1. DENV NS1 binds to platelet. 25
4.2. Colocalization of DENV NS1 and TLR4 on platelets surface. 25
4.3. DENV NS1 induces platelet activation. 26
4.4. Signal pathway other than TLR4 may also involve in DENV NS1-induced platelet activation. 27
4.5. DENV NS1 induces apoptosis of platelet. 28
4.6. NS1-increased P-selectin expression can be inhibited by ROS inhibitor. 29
4.7. DENV NS1 increases platelet adhesion on leukocyte. 30
4.8. DENV NS1-stimulated platelet may increase endothelium permeability. 31
5. Discussion 33
6. Conclusion 40
7. References 41
8. Figures 54

參考文獻 Akey, D. L., Brown, W. C., Dutta, S., Konwerski, J., Jose, J., Jurkiw, T. J., . . . Smith, J. L. (2014). Flavivirus NS1 structures reveal surfaces for associations with membranes and the immune system. Science, 343(6173), 881-885. doi:10.1126/science.1247749
Al Ghumlas, A. K., & Gader, A. G. M. A. (2013). The blood platelet: An intriguing cell. J Appl Hematol, 4:1-12.
Alcon, S., Talarmin, A., Debruyne, M., Falconar, A., Deubel, V., & Flamand, M. (2002). Enzyme-linked immunosorbent assay specific to Dengue virus type 1 nonstructural protein NS1 reveals circulation of the antigen in the blood during the acute phase of disease in patients experiencing primary or secondary infections. J Clin Microbiol, 40(2), 376-381.
Andonegui, G., Kerfoot, S. M., McNagny, K., Ebbert, K. V., Patel, K. D., & Kubes, P. (2005). Platelets express functional Toll-like receptor-4. Blood, 106(7), 2417-2423. doi:10.1182/blood-2005-03-0916
Avirutnan, P., Fuchs, A., Hauhart, R. E., Somnuke, P., Youn, S., Diamond, M. S., & Atkinson, J. P. (2010). Antagonism of the complement component C4 by flavivirus nonstructural protein NS1. J Exp Med, 207(4), 793-806. doi:10.1084/jem.20092545
Avirutnan, P., Hauhart, R. E., Somnuke, P., Blom, A. M., Diamond, M. S., & Atkinson, J. P. (2011). Binding of flavivirus nonstructural protein NS1 to C4b binding protein modulates complement activation. J Immunol, 187(1), 424-433. doi:10.4049/jimmunol.1100750
Beatty, P. R., Puerta-Guardo, H., Killingbeck, S. S., Glasner, D. R., Hopkins, K., & Harris, E. (2015). Dengue virus NS1 triggers endothelial permeability and vascular leak that is prevented by NS1 vaccination. Sci Transl Med, 7(304), 304ra141. doi:10.1126/scitranslmed.aaa3787
Bhatt, S., Gething, P. W., Brady, O. J., Messina, J. P., Farlow, A. W., Moyes, C. L., . . . Hay, S. I. (2013). The global distribution and burden of dengue. Nature, 496(7446), 504-507. doi:10.1038/nature12060
Bittencourt, C., Bittencourt, P., Neto, O., & Arenas, G. (2014). The use of platelet-rich plasma in orthopaedic injuries Platelet-Rich Plasma (pp. 289-313): Springer.
Bouchard, B. A., & Tracy, P. B. (2001). Platelets, leukocytes, and coagulation. Curr Opin Hematol, 8(5), 263-269.
Burke, D. S., Nisalak, A., Johnson, D. E., & Scott, R. M. (1988). A prospective study of dengue infections in Bangkok. Am J Trop Med Hyg, 38(1), 172-180.
Carter, P. J. (2006). Potent antibody therapeutics by design. Nat Rev Immunol, 6(5), 343-357. doi:10.1038/nri1837
Chan, K. R., Ong, E. Z., & Ooi, E. E. (2013). Therapeutic antibodies as a treatment option for dengue fever. Expert Rev Anti Infect Ther, 11(11), 1147-1157. doi:10.1586/14787210.2013.839941
Chen, H. R., Chuang, Y. C., Lin, Y. S., Liu, H. S., Liu, C. C., Perng, G. C., & Yeh, T. M. (2016). Dengue Virus Nonstructural Protein 1 Induces Vascular Leakage through Macrophage Migration Inhibitory Factor and Autophagy. PLoS Negl Trop Dis, 10(7), e0004828. doi:10.1371/journal.pntd.0004828
Choi, J. L., Li, S., & Han, J. Y. (2014). Platelet function tests: a review of progresses in clinical application. Biomed Res Int, 2014, 456569. doi:10.1155/2014/456569
Chuang, Y. C., Lei, H. Y., Liu, H. S., Lin, Y. S., Fu, T. F., & Yeh, T. M. (2011). Macrophage migration inhibitory factor induced by dengue virus infection increases vascular permeability. Cytokine, 54(2), 222-231. doi:10.1016/j.cyto.2011.01.013
Ciesienski, K. L., & Caravan, P. (2011). Molecular MRI of thrombosis. Curr Cardiovasc Imaging Rep, 4(1), 77-84.
Coller, B. S., & Shattil, S. J. (2008). The GPIIb/IIIa (integrin alphaIIbbeta3) odyssey: a technology-driven saga of a receptor with twists, turns, and even a bend. Blood, 112(8), 3011-3025. doi:10.1182/blood-2008-06-077891
Danielli, J. (1940). Capillary permeability and oedema in the perfused frog. J Physiol, 98(1), 109-129.
Davis, B. K., Wen, H., & Ting, J. P. (2011). The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol, 29, 707-735. doi:10.1146/annurev-immunol-031210-101405
de Azeredo, E. L., Monteiro, R. Q., & de-Oliveira Pinto, L. M. (2015). Thrombocytopenia in Dengue: Interrelationship between Virus and the Imbalance between Coagulation and Fibrinolysis and Inflammatory Mediators. Mediators Inflamm, 2015, 313842. doi:10.1155/2015/313842
Endy, T. P., Chunsuttiwat, S., Nisalak, A., Libraty, D. H., Green, S., Rothman, A. L., . . . Ennis, F. A. (2002). Epidemiology of inapparent and symptomatic acute dengue virus infection: a prospective study of primary school children in Kamphaeng Phet, Thailand. Am J Epidemiol, 156(1), 40-51.
Estaquier, J., Vallette, F., Vayssiere, J. L., & Mignotte, B. (2012). The mitochondrial pathways of apoptosis. Adv Exp Med Biol, 942, 157-183. doi:10.1007/978-94-007-2869-1_7
Flaujac, C., Boukour, S., & Cramer-Borde, E. (2010). Platelets and viruses: an ambivalent relationship. Cell Mol Life Sci, 67(4), 545-556. doi:10.1007/s00018-009-0209-x
Fleury, C., Mignotte, B., & Vayssiere, J. L. (2002). Mitochondrial reactive oxygen species in cell death signaling. Biochimie, 84(2-3), 131-141.
Freedman, J. E. (2005). Molecular regulation of platelet-dependent thrombosis. Circulation, 112(17), 2725-2734. doi:10.1161/circulationaha.104.494468
Geraldo, R. B., Sathler, P. C., Lourenço, A. L., Saito, M. S., Cabral, L. M., Rampelotto, P. H., & Castro, H. C. (2014). Platelets: still a therapeutical target for haemostatic disorders. Int J Mol Sci, 15(10), 17901-17919. doi:10.3390/ijms151017901.
Ghosh, K., Gangodkar, S., Jain, P., Shetty, S., Ramjee, S., Poddar, P., & Basu, A. (2008). Imaging the interaction between dengue 2 virus and human blood platelets using atomic force and electron microscopy. J Electron Microsc (Tokyo), 57(3), 113-118. doi:10.1093/jmicro/dfn007
Ghoshal, K., & Bhattacharyya, M. (2014). Overview of platelet physiology: its hemostatic and nonhemostatic role in disease pathogenesis. ScientificWorldJournal, 2014, 781857. doi:10.1155/2014/781857
Guzman, M. G., Halstead, S. B., Artsob, H., Buchy, P., Farrar, J., Gubler, D. J., . . . Peeling, R. W. (2010). Dengue: a continuing global threat. Nat Rev Microbiol, 8(12 Suppl), S7-16. doi:10.1038/nrmicro2460
Halstead, S. B. (2007). Dengue. Lancet, 370(9599), 1644-1652. doi:10.1016/s0140-6736(07)61687-0
Halstead, S. B., & O'Rourke, E. J. (1977a). Antibody-enhanced dengue virus infection in primate leukocytes. Nature, 265(5596), 739-741.
Halstead, S. B., & O'Rourke, E. J. (1977b). Dengue viruses and mononuclear phagocytes. I. Infection enhancement by non-neutralizing antibody. J Exp Med, 146(1), 201-217.
Hartwig, J. H. (2002). Platelet structure. Platelets, 1(3752), 26.
Henchal, E. A., & Putnak, J. R. (1990). The dengue viruses. Clin Microbiol Rev, 3(4), 376-396.
Honda, S., Saito, M., Dimaano, E. M., Morales, P. A., Alonzo, M. T., Suarez, L. A., . . . Oishi, K. (2009). Increased phagocytosis of platelets from patients with secondary dengue virus infection by human macrophages. Am J Trop Med Hyg, 80(5), 841-845.
Hornef, M. W., Normark, B. H., Vandewalle, A., & Normark, S. (2003). Intracellular recognition of lipopolysaccharide by toll-like receptor 4 in intestinal epithelial cells. J Exp Med, 198(8), 1225-1235. doi:10.1084/jem.20022194
Hottz, E. D., Lopes, J. F., Freitas, C., Valls-de-Souza, R., Oliveira, M. F., Bozza, M. T., . . . Bozza, F. A. (2013). Platelets mediate increased endothelium permeability in dengue through NLRP3-inflammasome activation. Blood, 122(20), 3405-3414.
Hottz, E. D., Medeiros-de-Moraes, I. M., Vieira-de-Abreu, A., de Assis, E. F., Vals-de-Souza, R., Castro-Faria-Neto, H. C., . . . Bozza, P. T. (2014). Platelet activation and apoptosis modulate monocyte inflammatory responses in dengue. J Immunol, 193(4), 1864-1872. doi:10.4049/jimmunol.1400091
Hottz, E. D., Oliveira, M. F., Nunes, P. C., Nogueira, R. M., Valls-de-Souza, R., Da Poian, A. T., . . . Bozza, F. A. (2013). Dengue induces platelet activation, mitochondrial dysfunction and cell death through mechanisms that involve DC-SIGN and caspases. J Thromb Haemost, 11(5), 951-962. doi:10.1111/jth.12178
Houghton-Trivino, N., Martin, K., Giaya, K., Rodriguez, J. A., Bosch, I., & Castellanos, J. E. (2010). [Comparison of the transcriptional profiles of patients with dengue fever and dengue hemorrhagic fever reveals differences in the immune response and clues in immunopathogenesis]. Biomedica, 30(4), 587-597.
Kho, L. K., Wulur, H., & Himawan, T. (1972). Blood and bone marrow changes in dengue haemorrhagic fever. Paediatr Indones, 12(1), 31-39.
Kirkpatrick, B. D., Whitehead, S. S., Pierce, K. K., Tibery, C. M., Grier, P. L., Hynes, N. A., . . . Durbin, A. P. (2016). The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model. Sci Transl Med, 8(330), 330ra336. doi:10.1126/scitranslmed.aaf1517
Krishnamurti, C., Peat, R. A., Cutting, M. A., & Rothwell, S. W. (2002). Platelet adhesion to dengue-2 virus-infected endothelial cells. Am J Trop Med Hyg, 66(4), 435-441.
Kummerer, B. M., & Rice, C. M. (2002). Mutations in the yellow fever virus nonstructural protein NS2A selectively block production of infectious particles. J Virol, 76(10), 4773-4784.
Lamkanfi, M., & Dixit, V. M. (2011). Modulation of inflammasome pathways by bacterial and viral pathogens. J Immunol, 187(2), 597-602. doi:10.4049/jimmunol.1100229
Leytin, V., Allen, D. J., Mutlu, A., Mykhaylov, S., Lyubimov, E., & Freedman, J. (2008). Platelet activation and apoptosis are different phenomena: evidence from the sequential dynamics and the magnitude of responses during platelet storage. Br J Haematol, 142(3), 494-497. doi:10.1111/j.1365-2141.2008.07209.x
Libraty, D. H., Young, P. R., Pickering, D., Endy, T. P., Kalayanarooj, S., Green, S., . . . Rothman, A. L. (2002). 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. doi:10.1086/343813
Lin, C. C., Huang, Y. H., Shu, P. Y., Wu, H. S., Lin, Y. S., Yeh, T. M., . . . Lei, H. Y. (2010). Characteristic of dengue disease in Taiwan: 2002-2007. Am J Trop Med Hyg, 82(4), 731-739. doi:10.4269/ajtmh.2010.09-0549
Lin, C. F., Lei, H. Y., Liu, C. C., Liu, H. S., Yeh, T. M., Wang, S. T., . . . Lin, Y. S. (2001). Generation of IgM anti-platelet autoantibody in dengue patients. J Med Virol, 63(2), 143-149.
Lin, S. W., Chuang, Y. C., Lin, Y. S., Lei, H. Y., Liu, H. S., & Yeh, T. M. (2012). Dengue virus nonstructural protein NS1 binds to prothrombin/thrombin and inhibits prothrombin activation. J Infect, 64(3), 325-334. doi:10.1016/j.jinf.2011.11.023
Lin, Y. S., Yeh, T. M., Lin, C. F., Wan, S. W., Chuang, Y. C., Hsu, T. K., . . . Lei, H. Y. (2011). Molecular mimicry between virus and host and its implications for dengue disease pathogenesis. Exp Biol Med (Maywood), 236(5), 515-523. doi:10.1258/ebm.2011.010339
Mackenzie, J. M., Jones, M. K., & Young, P. R. (1996). Immunolocalization of the dengue virus nonstructural glycoprotein NS1 suggests a role in viral RNA replication. Virology, 220(1), 232-240. doi:10.1006/viro.1996.0307
Martinon, F., Petrilli, V., Mayor, A., Tardivel, A., & Tschopp, J. (2006). Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature, 440(7081), 237-241. doi:10.1038/nature04516
Mason, K. D., Carpinelli, M. R., Fletcher, J. I., Collinge, J. E., Hilton, A. A., Ellis, S., . . . Kile, B. T. (2007). Programmed anuclear cell death delimits platelet life span. Cell, 128(6), 1173-1186. doi:10.1016/j.cell.2007.01.037
Michels, M., Alisjahbana, B., De Groot, P. G., Indrati, A. R., Fijnheer, R., Puspita, M., . . . de Mast, Q. (2014). Platelet function alterations in dengue are associated with plasma leakage. Thromb Haemost, 112(2), 352-362. doi:10.1160/th14-01-0056
Modhiran, N., Watterson, D., Muller, D. A., Panetta, A. K., Sester, D. P., Liu, L., . . . Young, P. R. (2015). Dengue virus NS1 protein activates cells via Toll-like receptor 4 and disrupts endothelial cell monolayer integrity. Sci Transl Med, 7(304), 304ra142. doi:10.1126/scitranslmed.aaa3863
Morrison, J., Aguirre, S., & Fernandez-Sesma, A. (2012). Innate immunity evasion by Dengue virus. Viruses, 4(3), 397-413.
Muller, D. A., & Young, P. R. (2013). The flavivirus NS1 protein: molecular and structural biology, immunology, role in pathogenesis and application as a diagnostic biomarker. Antiviral Res, 98(2), 192-208. doi:10.1016/j.antiviral.2013.03.008
Nakao, S., Lai, C. J., & Young, N. S. (1989). Dengue virus, a flavivirus, propagates in human bone marrow progenitors and hematopoietic cell lines. Blood, 74(4), 1235-1240.
Noisakran, S., Gibbons, R. V., Songprakhon, P., Jairungsri, A., Ajariyakhajorn, C., Nisalak, A., . . . Perng, G. C. (2009). Detection of dengue virus in platelets isolated from dengue patients. Southeast Asian J Trop Med Public Health, 40(2), 253-262.
Ojha, A., Nandi, D., Batra, H., Singhal, R., Annarapu, G. K., Bhattacharyya, S., . . . Guchhait, P. (2017). Platelet activation determines the severity of thrombocytopenia in dengue infection. Sci Rep, 7, 41697. doi:10.1038/srep41697
Peeling, R. W., Artsob, H., Pelegrino, J. L., Buchy, P., Cardosa, M. J., Devi, S., . . . Yoksan, S. (2010). Evaluation of diagnostic tests: dengue. Nat Rev Microbiol, 8(12 Suppl), S30-38. doi:10.1038/nrmicro2459
Puerta-Guardo, H., Glasner, D. R., & Harris, E. (2016). Dengue Virus NS1 Disrupts the Endothelial Glycocalyx, Leading to Hyperpermeability. PLoS Pathog, 12(7), e1005738. doi:10.1371/journal.ppat.1005738
Rodenhuis-Zybert, I. A., van der Schaar, H. M., da Silva Voorham, J. M., van der Ende-Metselaar, H., Lei, H. Y., Wilschut, J., & Smit, J. M. (2010). Immature dengue virus: a veiled pathogen? PLoS Pathog, 6(1), e1000718. doi:10.1371/journal.ppat.1000718
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. doi:10.1038/nri3014
Shrivastava, A., Dash, P. K., Tripathi, N. K., Sahni, A. K., Gopalan, N., & Lakshmana Rao, P. V. (2011). Evaluation of a commercial Dengue NS1 enzyme-linked immunosorbent assay for early diagnosis of dengue infection. Indian J Med Microbiol, 29(1), 51-55. doi:10.4103/0255-0857.76525
Siess, W. (1989). Molecular mechanisms of platelet activation. Physiol Rev, 69(1), 58-178.
Simon, A. Y., Sutherland, M. R., & Pryzdial, E. L. (2015). Dengue virus binding and replication by platelets. Blood, 126(3), 378-385. doi:10.1182/blood-2014-09-598029
Srichaikul, T., & Nimmannitya, S. (2000). Haematology in dengue and dengue haemorrhagic fever. Baillieres Best Pract Res Clin Haematol, 13(2), 261-276. doi:10.1053/beha.2000.0073
Suharti, C., van Gorp, E. C., Setiati, T. E., Dolmans, W. M., Djokomoeljanto, R. J., Hack, C. E., . . . van der Meer, J. W. (2002). The role of cytokines in activation of coagulation and fibrinolysis in dengue shock syndrome. Thromb Haemost, 87(1), 42-46.
Vaure, C., & Liu, Y. (2014). A comparative review of toll-like receptor 4 expression and functionality in different animal species. Front Immunol, 5, 316. doi: 10.3389/fimmu.2014.00316
Versteeg, H. H., Heemskerk, J. W., Levi, M., & Reitsma, P. H. (2013). New fundamentals in hemostasis. Physiol Rev, 93(1), 327-358.
Visintin, A., Mazzoni, A., Spitzer, J. H., Wyllie, D. H., Dower, S. K., & Segal, D. M. (2001). Regulation of Toll-like receptors in human monocytes and dendritic cells. J Immunol, 166(1), 249-255.
Wan, S. W., Lu, Y. T., Huang, C. H., Lin, C. F., Anderson, R., Liu, H. S., . . . Lin, Y. S. (2014). Protection against dengue virus infection in mice by administration of antibodies against modified nonstructural protein 1. PLoS One, 9(3), e92495. doi:10.1371/journal.pone.0092495
Wan, S. W., Yang, Y. W., Chu, Y. T., Lin, C. F., Chang, C. P., Yeh, T. M., . . . Lin, Y. S. (2016). Anti-dengue virus nonstructural protein 1 antibodies contribute to platelet phagocytosis by macrophages. Thromb Haemost, 115(3), 646-656. doi:10.1160/th15-06-0498
Wang, S. F., Wang, W. H., Chang, K., Chen, Y. H., Tseng, S. P., Yen, C. H., . . . Chen, Y. M. (2016). Severe Dengue Fever Outbreak in Taiwan. Am J Trop Med Hyg, 94(1), 193-197. doi:10.4269/ajtmh.15-0422
White, J. G. (1979). Current concepts of platelet structure. Am J Clin Pathol, 71(4), 363-378.
Wraith, K. S., Magwenzi, S., Aburima, A., Wen, Y., Leake, D., & Naseem, K. M. (2013). Oxidized low-density lipoproteins induce rapid platelet activation and shape change through tyrosine kinase and Rho kinase-signaling pathways. Blood, 122(4), 580-589. doi:10.1182/blood-2013-04-491688
Wu, S. F., Liao, C. L., Lin, Y. L., Yeh, C. T., Chen, L. K., Huang, Y. F., . . . Sytwu, H. K. (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.
Yan, M., Lesyk, G., Radziwon-Balicka, A., & Jurasz, P. (2014). Pharmacological regulation of platelet factors that influence tumor angiogenesis. Semin Oncol, 41(3):370-7. doi:10.1053/j.seminoncol.2014.04.007.
Yang, C. F., Hou, J. N., Chen, T. H., & Chen, W. J. (2014). Discriminable roles of Aedes aegypti and Aedes albopictus in establishment of dengue outbreaks in Taiwan. Acta Trop, 130, 17-23. doi:10.1016/j.actatropica.2013.10.013
Young, P. R., Hilditch, P. A., Bletchly, C., & Halloran, W. (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.
Zhang, G., Han, J., Welch, E. J., Richard, D. Y., Voyno-Yasenetskaya, T. A., Malik, A. B., . . . Li, Z. (2009). Lipopolysaccharide stimulates platelet secretion and potentiates platelet aggregation via TLR4/MyD88 and the cGMP-dependent protein kinase pathway. J Immunol, 182(12), 7997-8004. doi: 10.4049/jimmunol.0802884.
Zhou, R., Yazdi, A. S., Menu, P., & Tschopp, J. (2011). A role for mitochondria in NLRP3 inflammasome activation. Nature, 469(7329), 221-225. doi:10.1038/nature09663
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2022-07-04起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2022-07-04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