登革病毒(DENV)是最普遍的蚊媒病毒之一。當宿主被登革病毒感染時，大多數的人會傾向發展成輕微的症狀，像是登革熱；但是少部分的人可能會發展成較嚴重的症狀，像是登革出血熱或登革休克症候群。然而，目前對於登革病毒所導致的致病機制並不是很清楚。在登革病毒感染時，許多RNA的感應器，包括RIG-I、MDA5、TLR3與TLR7，都已經證實可以偵測病毒的RNA進而活化第一型干擾素與促發炎細胞激素進而抗病毒防禦。同時，登革病毒的非結構蛋白會打斷宿主抗病毒反應進而促進病毒在宿主體內的複製。一個先天免疫的調節器TAPE (TBK1-Associated Protein in Endolysosomes) 已知參與在TLR3、TLR4與RLR 活化路徑中。因此我們想要去探討是否TAPE是否在登革病毒感染時在這些RNA感應器中對於活化第一型干擾素扮演著重要的角色。我們的結果指出在TAPE剔除的情況下，在登革病毒感染時RLR介導的IFN-β活化會受到影響。除此之外，在TAPE 剔除的人類單核球分化成的巨噬細胞中，當給予登革病毒感染可以發現IFN-β與IP-10的活化會顯著的抑制。然而在登革病毒感染TAPE基因剔除的老鼠胚胎纖維母細胞中可以發現干擾素與促發炎激素會顯著的抑制。但是，我們在體內實驗中發現在登革病毒感染時WT與TAPE剔除的小鼠體重隨著時間並無顯著差異。總和我們的結果顯示在初代細胞與哺乳動物細胞中TAPE會參與RLR路徑去促使第一型干擾素進而抗病毒反應有關。未來我們需要進一步證實在對抗登革病毒感染時TAPE扮演的重要角色。有鑑於C型凝集素受體CLEC5A在登革病毒感染時會誘發發炎，我們想進一步探討是否在登革病毒感染時細胞表面的TLRs會參與在免疫調節機制中。我們結果顯示在HEK293細胞中異位表達TLR4會增強登革病毒感染與病毒RNA的複製。因此我們推測TLR4可能在登革病毒感染時扮演著接受器的角色。總結上述結果，我們目前的研究提供一個新的先天免疫調節因子在早期會影響干擾素的活化進而促進病毒的複製。

Dengue Virus (DENV) infection is one of the most prevailing vector-borne infectious diseases. When infected with DENV, some patients develop mild symptoms like dengue fever, but some may develop severe syndromes like dengue hemorrhagic fever or dengue septic shock. However, the mechanisms underlying DENV pathogenesis are still unclear. Upon DENV infection, several RNA sensors, including RIG-I, MDA5, TLR3 and TLR7, are shown to detect DENV viral RNA to induce type I IFNs and pro-inflammatory cytokines for antiviral defenses. Meanwhile, DENV non-structural protein (NS) proteins are shown to counteract the host antiviral responses to promote viral replication. An innate immune regulator TBK1-Associated Protein in Endolysosomes (TAPE) is shown to involve in the TLR3, TLR4, and RIG-I-like receptor (RLR) pathways. Thus, we attempted to explore whether TAPE plays a critical role in regulating these RNA sensor pathways to type-I IFN production during DENV infection. Our results indicated that TAPE knockdown impaired RLR-mediated IFN-β activation upon DENV infection. In addition, knockdown of TAPE in human monocyte-derived macrophages significantly decreased human type I IFNs and IP-10 activation during DENV infection. Studies from TAPE knockout MEFs showed that the TAPE deficiency led to the significant decrease of IFN-β and RANTES. However, results from in vivo DENV infection showed that wild type (WT) and TAPE-deficiency mice showed similar body weight decrease during the course of DENV infection. Together, our data support a critical role for TAPE in linking the RLR pathways to type-I IFN antiviral responses in primary cells and mammalian cells. Further study is needed to determine in vivo importance of TAPE in defending DENV infection. Given the role of a C-type lectin receptor CLEC5A in DENV-induced inflammation, we was interested in exploring whether surface TLRs are implicated in innate immune regulation during DENV infection. Our results suggest that ectopic expression of TLR4 in HEK293 cells enhanced DENV infection and its viral RNA replication. Thus, we speculate that TLR4 might act as an entry receptor for DENV infection. In conclusion, our current works provide novel insights into the innate immune responses to DENV infection at the early stage.

1 Organization, W. H. GLOBAL STRATEGY FOR DENGUE PREVENTION AND CONTROL. WHO Library Cataloguing (2012).
2 Guzman, M. G. & Harris, E. Dengue. The Lancet 385, 453-465, doi:10.1016/s0140-6736(14)60572-9 (2015).
3 Screaton, G., Mongkolsapaya, J., Yacoub, S. & Roberts, C. New insights into the immunopathology and control of dengue virus infection. Nature reviews. Immunology 15, 745-759, doi:10.1038/nri3916 (2015).
4 Herrero, L. J. et al. Dengue virus therapeutic intervention strategies based on viral, vector and host factors involved in disease pathogenesis. Pharmacology & therapeutics 137, 266-282, doi:10.1016/j.pharmthera.2012.10.007 (2013).
5 Cameron P. Simmons, P. D., Jeremy J. Farrar, M.D., Ph.D., Nguyen van Vinh Chau, M.D., Ph.D., and Bridget Wills, M.D., D.M. dengue. T h e new engl and journa l o f medicine 366, 1423-1432 (2012).
6 Whitehead, S. S., Blaney, J. E., Durbin, A. P. & Murphy, B. R. Prospects for a dengue virus vaccine. Nature reviews. Microbiology 5, 518-528, doi:10.1038/nrmicro1690 (2007).
7 WHO. Dengue. (2009).
8 H.A.F. Stephens, R. K., M. Sirikong, D.W. Vaughn, S. Green, S. Kalayanarooj, T.P. Endy, D.H. Libraty, A. Nisalak, B.L. Innis, A.L. Rothman, F.A. Ennis andD. Chandanayingyong. HLA-A and -B allele associations with secondary dengue virus infections correlate with disease severity and the infecting viral serotype in ethnic Thais. Tissue Antigens Immune Response Genetics 60, 309–318 (2002).
9 Chao, Y. C. et al. Higher infection of dengue virus serotype 2 in human monocytes of patients with G6PD deficiency. PloS one 3, e1557, doi:10.1371/journal.pone.0001557 (2008).
10 Pang, J. et al. Diabetes with hypertension as risk factors for adult dengue hemorrhagic fever in a predominantly dengue serotype 2 epidemic: a case control study. PLoS neglected tropical diseases 6, e1641, doi:10.1371/journal.pntd.0001641 (2012).
11 Anders, K. L. et al. Epidemiological factors associated with dengue shock syndrome and mortality in hospitalized dengue patients in Ho Chi Minh City, Vietnam. The American journal of tropical medicine and hygiene 84, 127-134, doi:10.4269/ajtmh.2011.10-0476 (2011).
12 Figueiredo, M. A. et al. Allergies and diabetes as risk factors for dengue hemorrhagic fever: results of a case control study. PLoS neglected tropical diseases 4, e699, doi:10.1371/journal.pntd.0000699 (2010).
13 Anne Tuiskunen Bäck, P. a. Å. L., Professor. Dengue viruses an overview. infection ecology & epidemiology 3, doi:10.3402/iee.v3i0.19839 (2013).
14 Mondotte, J. A., Lozach, P. Y., Amara, A. & Gamarnik, A. V. Essential role of dengue virus envelope protein N glycosylation at asparagine-67 during viral propagation. Journal of virology 81, 7136-7148, doi:10.1128/JVI.00116-07 (2007).
15 Bruno Guy, J. L., Melanie Saville, & Jackson, a. N. Vaccination Against Dengue: Challenges and Current Developments. Annual Review, doi:10.1146/annurev-med-091014-090848 (2015).
16 Martina, B. E., Koraka, P. & Osterhaus, A. D. Dengue virus pathogenesis: an integrated view. Clinical microbiology reviews 22, 564-581, doi:10.1128/CMR.00035-09 (2009).
17 McNab, F., Mayer-Barber, K., Sher, A., Wack, A. & O'Garra, A. Type I interferons in infectious disease. Nature reviews. Immunology 15, 87-103, doi:10.1038/nri3787 (2015).
18 Kawasaki, T. & Kawai, T. Toll-like receptor signaling pathways. Frontiers in immunology 5, 461, doi:10.3389/fimmu.2014.00461 (2014).
19 Lester, S. N. & Li, K. Toll-like receptors in antiviral innate immunity. Journal of molecular biology 426, 1246-1264, doi:10.1016/j.jmb.2013.11.024 (2014).
20 O'Neill, L. A., Golenbock, D. & Bowie, A. G. The history of Toll-like receptors - redefining innate immunity. Nature reviews. Immunology 13, 453-460, doi:10.1038/nri3446 (2013).
21 Wu, J. & Chen, Z. J. Innate immune sensing and signaling of cytosolic nucleic acids. Annual review of immunology 32, 461-488, doi:10.1146/annurev-immunol-032713-120156 (2014).
22 Hoffmann, H. H., Schneider, W. M. & Rice, C. M. Interferons and viruses: an evolutionary arms race of molecular interactions. Trends in immunology 36, 124-138, doi:10.1016/j.it.2015.01.004 (2015).
23 Ivashkiv, L. B. & Donlin, L. T. Regulation of type I interferon responses. Nature reviews. Immunology 14, 36-49, doi:10.1038/nri3581 (2014).
24 Goubau, D., Deddouche, S. & Reis e Sousa, C. Cytosolic sensing of viruses. Immunity 38, 855-869, doi:10.1016/j.immuni.2013.05.007 (2013).
25 Iwasaki, A. & Medzhitov, R. Toll-like receptor control of the adaptive immune responses. Nature immunology 5, 987-995, doi:10.1038/ni1112 (2004).
26 Barton, G. M. & Kagan, J. C. A cell biological view of Toll-like receptor function: regulation through compartmentalization. Nature reviews. Immunology 9, 535-542, doi:10.1038/nri2587 (2009).
27 Chow, J., Franz, K. M. & Kagan, J. C. PRRs are watching you: Localization of innate sensing and signaling regulators. Virology 479-480, 104-109, doi:10.1016/j.virol.2015.02.051 (2015).
28 Fenton, S. B. a. M. J. Toll-like receptors: function and roles in lung disease. American Physiological society 286, 887-892 (2004).
29 Melchjorsen, J. Learning from the messengers: innate sensing of viruses and cytokine regulation of immunity - clues for treatments and vaccines. Viruses 5, 470-527, doi:10.3390/v5020470 (2013).
30 Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nature immunology 11, 373-384, doi:10.1038/ni.1863 (2010).
31 Paludan, S. R. & Bowie, A. G. Immune sensing of DNA. Immunity 38, 870-880, doi:10.1016/j.immuni.2013.05.004 (2013).
32 Göertz, Giel P. & Pijlman, Gorben P. Dengue Non-coding RNA: TRIMmed for Transmission. Cell host & microbe 18, 133-134, doi:10.1016/j.chom.2015.07.009 (2015).
33 Yoandris del Toro Duany, Bin Wu, Sun Hur. MDA5 — filament, dynamics and disease. doi:10.1016/j.coviro.2015.01.011 (2015).
34 Taro Kawai et al. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nature immunology, doi:10.1038/ni1243 (2005).
35 Seth, R. B., Sun, L., Ea, C. K. & Chen, Z. J. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122, 669-682, doi:10.1016/j.cell.2005.08.012 (2005).
36 Meylan, E. et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437, 1167-1172, doi:10.1038/nature04193 (2005).
37 Xu, L. G. et al. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell 19, 727-740, doi:10.1016/j.molcel.2005.08.014 (2005).
38 Schlee, M. Master sensors of pathogenic RNA - RIG-I like receptors. Immunobiology 218, 1322-1335, doi:10.1016/j.imbio.2013.06.007 (2013).
39 Vazquez, C. & Horner, S. M. MAVS Coordination of Antiviral Innate Immunity. Journal of virology 89, 6974-6977, doi:10.1128/JVI.01918-14 (2015).
40 Loo, Y. M. et al. Distinct RIG-I and MDA5 signaling by RNA viruses in innate immunity. Journal of virology 82, 335-345, doi:10.1128/JVI.01080-07 (2008).
41 Raphaële Germia, b., Jean-Marc Cranceb, Daniel Garinb, 1, Josette Guimeta, Hugues Lortat-Jacobc, Rob W.H. Ruigroka, d, Jean-Pierre Zarskie, Emmanuel Droueta. Heparan Sulfate-Mediated Binding of Infectious DV2 and YFV. Virology, doi:10.1006/viro.2001.1232 (2002).
42 Yaping Chen, T. M., Ronald E. Hileman, Jonathan R. Fromm, Jeffrey D. Esko, Robert J. Linhardt & Rory M. Marks. Dengue virus infectivity depends on envelope protein binding to target cell heparan sulfate. Nature medicine 3, 866 - 871 (1997).
43 Luisa Martı´nez-Pomares‡§¶, J. A. M., Rita Ka´poszta‡i, Sheena A. Linehan‡, & Philip D. Stahl**, a. S. G. A Functional Soluble Form of the Murine Mannose Receptor Is Produced by Macrophages in Vitro and Is Present in Mouse Serum. The Journal of biological chemistry 273 (1998).
44 Taylor, P. R., Gordon, S. & Martinez-Pomares, L. The mannose receptor: linking homeostasis and immunity through sugar recognition. Trends in immunology 26, 104-110, doi:10.1016/j.it.2004.12.001 (2005).
45 Miller, J. L. et al. The mannose receptor mediates dengue virus infection of macrophages. PLoS pathogens 4, e17, doi:10.1371/journal.ppat.0040017 (2008).
46 Teunis B.H Geijtenbeek, R. T., Sandra J van Vliet, Gerard C.F van Duijnhoven, Gosse J Adema, Yvette van Kooyk*correspondenceemail, Carl G Figdor. Identification of DC-SIGN, a Novel Dendritic Cell–Specific ICAM-3 Receptor that Supports Primary Immune Responses. Cell 100, 575–585 (2000).
47 Kwan, W. H. et al. Dermal-type macrophages expressing CD209/DC-SIGN show inherent resistance to dengue virus growth. PLoS neglected tropical diseases 2, e311, doi:10.1371/journal.pntd.0000311 (2008).
48 BENSON M. CURTIS, S. S., AND ANDREW J. WATSON. Sequence and expression of a membrane-associated C-type lectin that exhibits CD4-independent binding of human immunodeficiency virus envelope glycoprotein gpl20. Proc. Natd. Acad. Sci. 89, 8356-8360 (1992).
49 Geijtenbeek, T. B. et al. Identification of different binding sites in the dendritic cell-specific receptor DC-SIGN for intercellular adhesion molecule 3 and HIV-1. The Journal of biological chemistry 277, 11314-11320, doi:10.1074/jbc.M111532200 (2002).
50 Pohlmann, S. et al. Hepatitis C Virus Glycoproteins Interact with DC-SIGN and DC-SIGNR. Journal of virology 77, 4070-4080, doi:10.1128/jvi.77.7.4070-4080.2003 (2003).
51 Lozach, P. Y. et al. DC-SIGN and L-SIGN are high affinity binding receptors for hepatitis C virus glycoprotein E2. The Journal of biological chemistry 278, 20358-20366, doi:10.1074/jbc.M301284200 (2003).
52 Navarro-Sanchez, E. et al. Dendritic-cell-specific ICAM3-grabbing non-integrin is essential for the productive infection of human dendritic cells by mosquito-cell-derived dengue viruses. EMBO reports 4, 723-728, doi:10.1038/sj.embor.embor866 (2003).
53 Tassaneetrithep, B. et al. DC-SIGN (CD209) mediates dengue virus infection of human dendritic cells. The Journal of experimental medicine 197, 823-829, doi:10.1084/jem.20021840 (2003).
54 Wang, L. et al. DC-SIGN (CD209) Promoter -336 A/G polymorphism is associated with dengue hemorrhagic fever and correlated to DC-SIGN expression and immune augmentation. PLoS neglected tropical diseases 5, e934, doi:10.1371/journal.pntd.0000934 (2011).
55 Roselynn Rodriguez-Manzanet, Rosemarie DeKruyff, Kuchroo, V. K. & Umetsu, a. T. The costimulatory role of TIM molecules. Immunological Reviews 229, 259-270 (2009).
56 Gordon J. Freeman, Jose M. Casasnovas, and, D. T. U. & DeKruyff, R. H. TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity. Immunological Reviews 235, 172-189 (2010).
57 Perera-Lecoin, M., Meertens, L., Carnec, X. & Amara, A. Flavivirus entry receptors: an update. Viruses 6, 69-88, doi:10.3390/v6010069 (2014).
58 Rothlin, G. L. C. V. Immunobiology of the TAM receptors. Nature Reviews Immunology 8, 327-336, doi:10.1038/nri2303 (2008).
59 Chen, S. T. et al. CLEC5A is critical for dengue-virus-induced lethal disease. Nature 453, 672-676, doi:10.1038/nature07013 (2008).
60 Wu, M. F. et al. CLEC5A is critical for dengue virus-induced inflammasome activation in human macrophages. Blood 121, 95-106, doi:10.1182/blood-2012-05-430090 (2013).
61 Watson, A. A. et al. Structural flexibility of the macrophage dengue virus receptor CLEC5A: implications for ligand binding and signaling. The Journal of biological chemistry 286, 24208-24218, doi:10.1074/jbc.M111.226142 (2011).
62 Kawamura, T., Ogawa, Y., Aoki, R. & Shimada, S. Innate and intrinsic antiviral immunity in skin. Journal of dermatological science 75, 159-166, doi:10.1016/j.jdermsci.2014.05.004 (2014).
63 Yi-Ting Tsai, C.-L. K., Sui-Yuan Chang,. Human TLR3 recognizes dengue virus and modulates viral replication in vitro. doi:10.1111/j.1462-5822.2008.01277.x (2009).
64 Wang, J. P. et al. Flavivirus Activation of Plasmacytoid Dendritic Cells Delineates Key Elements of TLR7 Signaling beyond Endosomal Recognition. The Journal of Immunology 177, 7114-7121, doi:10.4049/jimmunol.177.10.7114 (2006).
65 Yu, C. Y. et al. Dengue virus targets the adaptor protein MITA to subvert host innate immunity. PLoS pathogens 8, e1002780, doi:10.1371/journal.ppat.1002780 (2012).
66 Sun, P. et al. Functional characterization of ex vivo blood myeloid and plasmacytoid dendritic cells after infection with dengue virus. Virology 383, 207-215, doi:10.1016/j.virol.2008.10.022 (2009).
67 Trinchieri, G. Type I interferon: friend or foe? The Journal of experimental medicine 207, 2053-2063, doi:10.1084/jem.20101664 (2010).
68 Chen, K.-R. & Ling, P. Emerging Roles of an Innate Immune Regulator TAPE in the Toll-Like Receptor and RIG-I-Like Receptor Pathways. Inflammation and Immunity in Cancer, 63-74, doi:10.1007/978-4-431-55327-4_5 (2015).
69 Nakamura, A., Naito, M., Tsuruo, T. & Fujita, N. Freud-1/Aki1, a novel PDK1-interacting protein, functions as a scaffold to activate the PDK1/Akt pathway in epidermal growth factor signaling. Molecular and cellular biology 28, 5996-6009, doi:10.1128/MCB.00114-08 (2008).
70 Chang, C. H. et al. TBK1-associated protein in endolysosomes (TAPE) is an innate immune regulator modulating the TLR3 and TLR4 signaling pathways. The Journal of biological chemistry 286, 7043-7051, doi:10.1074/jbc.M110.164632 (2011).
71 Chen, K. R. et al. TBK1-associated protein in endolysosomes (TAPE)/CC2D1A is a key regulator linking RIG-I-like receptors to antiviral immunity. The Journal of biological chemistry 287, 32216-32221, doi:10.1074/jbc.C112.394346 (2012).
72 Xiao-Ming Ou*, S. L., Hamed Jafar-Nejad, Christopher D. Bown, Aya Goto, Anastasia Rogaeva, and Paul R. Albert. Freud-1: A Neuronal Calcium-Regulated Repressor of the 5-HT1A Receptor Gene. The Journal of Neuroscience 23, 7415-7425 (2003).
73 Usami, Y. et al. Regulation of CHMP4/ESCRT-III function in human immunodeficiency virus type 1 budding by CC2D1A. Journal of virology 86, 3746-3756, doi:10.1128/JVI.06539-11 (2012).
74 Chan, K. W. K., Watanabe, S., Kavishna, R., Alonso, S. & Vasudevan, S. G. Animal models for studying dengue pathogenesis and therapy. Antiviral research 123, 5-14, doi:10.1016/j.antiviral.2015.08.013 (2015).
75 Lee, Y. R. et al. Suckling mice were used to detect infectious dengue-2 viruses by intracerebral injection of the full-length RNA transcript. Intervirology 48, 161-166, doi:10.1159/000081744 (2005).
76 Chen, H. C. et al. Lymphocyte activation and hepatic cellular infiltration in immunocompetent mice infected by dengue virus. Journal of medical virology 73, 419-431, doi:10.1002/jmv.20108 (2004).
77 Ghosh Roy, S., Sadigh, B., Datan, E., Lockshin, R. A. & Zakeri, Z. Regulation of cell survival and death during Flavivirus infections. World journal of biological chemistry 5, 93-105, doi:10.4331/wjbc.v5.i2.93 (2014).
78 Kao-Jean Huang, S.-Y. J. L., Shiour-Ching Chen, Hsiao-Sheng Liu, Yee-Shin Lin, Trai-Ming Yeh, & Lei, C.-C. L. a. H.-Y. Manifestation of thrombocytopenia in dengue-2-virus-infected mice. (2000).
79 Perry, S. T., Buck, M. D., Lada, S. M., Schindler, C. & Shresta, S. STAT2 mediates innate immunity to Dengue virus in the absence of STAT1 via the type I interferon receptor. PLoS pathogens 7, e1001297, doi:10.1371/journal.ppat.1001297 (2011).
80 Sujan Shresta, K. L. S., Daniil M. Prigozhin, Heidi M. Snider, P. Robert Beatty,and Eva Harris. Critical Roles for Both STAT1-Dependent and STAT1-Independent pathways in the control of primary dengue virus infection in mice. The Journal of Immunology (2005).
81 Tan, G. K. et al. A non mouse-adapted dengue virus strain as a new model of severe dengue infection in AG129 mice. PLoS neglected tropical diseases 4, e672, doi:10.1371/journal.pntd.0000672 (2010).
82 Sujan Shresta, K. L. S., Daniil M. Prigozhin, P.Robert Beatty and Eva Harris. Murine Model for Dengue Virus-Induced Lethal Disease with Increased Vascular Permeability. doi:10.1128/JVI.00062-06 (2006).
83 Pinto, A. K. et al. Defining New Therapeutics Using a More Immunocompetent Mouse Model of Antibody-Enhanced Dengue Virus Infection. MBio 6, doi:10.1128/mBio.01316-15 (2015).
84 Zust, R. et al. Type I interferon signals in macrophages and dendritic cells control dengue virus infection: implications for a new mouse model to test dengue vaccines. Journal of virology 88, 7276-7285, doi:10.1128/JVI.03827-13 (2014).
85 Tyler R. Prestwood, M. M. M., Raphaël M. Zellweger, Robyn Miller, Monica M. May, Lauren E. Yauch, Steven M. Lada, and Sujan Shresta, 1 Jennifer L. Kyle, 1,2 Heidi M. Snider,1 Manasa Basavapatna,1. Gamma Interferon (IFN-γ) Receptor Restricts Systemic Dengue Virus Replication and Prevents Paralysis in IFN-α/β Receptor-Deficient Mice. Journal of virology 86, 12561-12570, doi:10.1128/JVI.06743-11 (2012).
86 Bente, D. A., Melkus, M. W., Garcia, J. V. & Rico-Hesse, R. Dengue fever in humanized NOD/SCID mice. Journal of virology 79, 13797-13799, doi:10.1128/JVI.79.21.13797-13799.2005 (2005).
87 Jaiswal, S. et al. Dengue virus infection and virus-specific HLA-A2 restricted immune responses in humanized NOD-scid IL2rgammanull mice. PloS one 4, e7251, doi:10.1371/journal.pone.0007251 (2009).
88 Javier Mota, R. R.-H. Dengue Virus Tropism in Humanized Mice Recapitulates Human Dengue Fever. PloS one 6, doi:10.1371/ (2011).
89 Chang, T. H. et al. Dengue virus serotype 2 blocks extracellular signal-regulated kinase and nuclear factor-kappaB activation to downregulate cytokine production. PloS one 7, e41635, doi:10.1371/journal.pone.0041635 (2012).
90 Ivan J. Fuss, M. E. K., Phillip D. Smith, Heddy Zola. Isolation of whole mononuclear cells from periperal blood and cord blood. Current Protocols in Immunology, doi:10.1002/0471142735.im0701s85 (2009).
91 Prestwood, T. R., Prigozhin, D. M., Sharar, K. L., Zellweger, R. M. & Shresta, S. A mouse-passaged dengue virus strain with reduced affinity for heparan sulfate causes severe disease in mice by establishing increased systemic viral loads. Journal of virology 82, 8411-8421, doi:10.1128/JVI.00611-08 (2008).
92 Nasirudeen, A. M. et al. RIG-I, MDA5 and TLR3 synergistically play an important role in restriction of dengue virus infection. PLoS neglected tropical diseases 5, e926, doi:10.1371/journal.pntd.0000926 (2011).
93 Broz, P. & Monack, D. M. Newly described pattern recognition receptors team up against intracellular pathogens. Nature reviews. Immunology 13, 551-565, doi:10.1038/nri3479 (2013).
94 SHUENN-JUE L. WU et al. Human skin Langerhans cells are targets of dengue virus infection. Nature Medicine 6, 816-820 (2000).
95 Srikiatkhachorn, A. et al. Dengue viral RNA levels in peripheral blood mononuclear cells are associated with disease severity and preexisting dengue immune status. PloS one 7, e51335, doi:10.1371/journal.pone.0051335 (2012).
96 Mercer, J. & Greber, U. F. Virus interactions with endocytic pathways in macrophages and dendritic cells. Trends in microbiology 21, 380-388, doi:10.1016/j.tim.2013.06.001 (2013).
97 Zellweger, R. M. & Shresta, S. Mouse models to study dengue virus immunology and pathogenesis. Frontiers in immunology 5, 151, doi:10.3389/fimmu.2014.00151 (2014).
98 Hsuen-Chin Chen, F. M. H., 2 John T. Kung,3 Yang-Ding Lin,1 and Betty A. Wu-Hsieh. Both Virus and Tumor Necrosis Factor Alpha Are Critical for Endothelium Damage in a Mouse Model of Dengue Virus-Induced Hemorrhage. doi:10.1128/JVI.02575-06 (2007).
99 Grace KX Tan, M. et al. Subcutaneous Infection with Non-mouse Adapted Dengue Virus D2Y98P Strain Induces Systemic Vascular Leakage in AG129 Mice. (2011).
100 Perry, S. T., Prestwood, T. R., Lada, S. M., Benedict, C. A. & Shresta, S. Cardif-mediated signaling controls the initial innate response to dengue virus in vivo. Journal of virology 83, 8276-8281, doi:10.1128/JVI.00365-09 (2009).
101 A Non Mouse-Adapted Dengue Virus Strain as a New Model of Severe Dengue Infection in AG129 Mice., doi:10.1371/journal.pntd.0000672.
102 Ashour, J. et al. Mouse STAT2 restricts early dengue virus replication. Cell host & microbe 8, 410-421, doi:10.1016/j.chom.2010.10.007 (2010).
103 Alen, M. M. et al. Antiviral activity of carbohydrate-binding agents and the role of DC-SIGN in dengue virus infection. Virology 387, 67-75, doi:10.1016/j.virol.2009.01.043 (2009).
104 Yun-Chi Chen, S.-Y. W. a. C.-C. K. Bacterial Lipopolysaccharide Inhibits Dengue Virus Infection of Primary Human Monocytes/Macrophages by Blockade of Virus Entry via a CD14-Dependent Mechanism. (1999).
105 Plociennikowska, A., Hromada-Judycka, A., Borzecka, K. & Kwiatkowska, K. Co-operation of TLR4 and raft proteins in LPS-induced pro-inflammatory signaling. Cellular and molecular life sciences : CMLS 72, 557-581, doi:10.1007/s00018-014-1762-5 (2015).
106 Yacoub, S., Mongkolsapaya, J. & Screaton, G. The pathogenesis of dengue. Current opinion in infectious diseases 26, 284-289, doi:10.1097/QCO.0b013e32835fb938 (2013).
107 Whitehorn, J. & Simmons, C. P. The pathogenesis of dengue. Vaccine 29, 7221-7228, doi:10.1016/j.vaccine.2011.07.022 (2011).
108 Chen, H. W. et al. The roles of IRF-3 and IRF-7 in innate antiviral immunity against dengue virus. Journal of immunology 191, 4194-4201, doi:10.4049/jimmunol.1300799 (2013).
109 Pierre Becquart , N. W., Dieudonné Nkoghe, Angélique Ndjoyi-Mbiguino, Cindy Padilla, Marc Souris, Eric M Leroy. Acute dengue virus 2 infection in Gabonese patients is associated with an early innate immune response, including strong interferon alpha production. BMC infectious diseases 10 (2010).
110 Hsieh, M. F. et al. Both CXCR3 and CXCL10/IFN-Inducible Protein 10 Are Required for Resistance to Primary Infection by Dengue Virus. The Journal of Immunology 177, 1855-1863, doi:10.4049/jimmunol.177.3.1855 (2006).
111 Sarathy, V. V., Milligan, G. N., Bourne, N. & Barrett, A. D. Mouse models of dengue virus infection for vaccine testing. Vaccine, doi:10.1016/j.vaccine.2015.09.112 (2015).
112 Aguirre, S. et al. DENV inhibits type I IFN production in infected cells by cleaving human STING. PLoS pathogens 8, e1002934, doi:10.1371/journal.ppat.1002934 (2012).
113 Sophie Alcon, A. T., Monique Debruyne, Andrew Falconar, Vincent Deubel,Marie Flamand1,. 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. Journal of Clinical Microbiology 40, 376-381, doi:10.1128/JCM.40.2.376-381.2002 (2002).
114 Chen, J., Ng, M. M. & Chu, J. J. Activation of TLR2 and TLR6 by Dengue NS1 Protein and Its Implications in the Immunopathogenesis of Dengue Virus Infection. PLoS pathogens 11, e1005053, doi:10.1371/journal.ppat.1005053 (2015).
115 Modhiran, N. et al. Dengue virus NS1 protein activates cells via Toll-like receptor 4 and disrupts endothelial cell monolayer integrity. Sci Transl Med 7, 304ra142, doi:10.1126/scitranslmed.aaa3863 (2015).
116 Djamiatun, K. et al. Toll-like receptor 4 polymorphisms in dengue virus-infected children. The American journal of tropical medicine and hygiene 85, 352-354, doi:10.4269/ajtmh.2011.10-0728 (2011).
117 Naphak Modhiran, D. W., David A. Muller, Adele K. Panetta, David P. Sester, & Lidong Liu, D. A. H., Katryn J. Stacey, Paul R. Young. Dengue virus NS1 protein activates cells via Toll-like receptor 4 and disrupts endothelial cell monolayer integrity. Science Translational Medicine 9 (2015).
118 Paul R. Young, Paige A. Hilditch, Cheryl Bletchly & Halloran, W. An Antigen Capture Enzyme-Linked Immunosorbent Assay Reveals High Levels of the Dengue Virus Protein NS1 in the Sera of Infected Patients. Journal of Clinical Microbiology 38, 1053-1057 (2000).
119 Bruno Guy et al. From research to phase III: Preclinical, industrial and clinical development of the Sanofi Pasteur tetravalent dengue vaccine. Vaccine 29, 7229-7241, doi:10.1016/j.vaccine.2011.06.094 (2011).
120 Laura M Snella, D. G. B. New insights into type I interferon and the immunopathogenesis of persistent viral infections. Current opinion in immunology 34, 91-98, doi:10.1016/j.coi.2015.03.002 (2015).
121 Reed, S. G., Orr, M. T. & Fox, C. B. Key roles of adjuvants in modern vaccines. Nature medicine 19, 1597-1608, doi:10.1038/nm.3409 (2013).