Re-evaluation of the pathogenic roles of nonstructural protein 1 and its antibodies during dengue virus infection

Journal of Biomedical Science

Trai-Ming Yeh⁴  Hong-Ru Chen³  Yee-Shin Lin¹  Shu-Ying Wang¹  Yung-Chun Chuang² 

[1] Department of Microbiology and Immunology, Medical College, National Cheng Kung University, Tainan, Taiwan;Center of Infectious Disease and Signaling Research, Medical College, National Cheng Kung University, Tainan, Taiwan;Institute of Basic Medical Sciences, Medical College, National Cheng Kung University, Tainan, Taiwan;Department of Medical Laboratory Science and Biotechnology, Medical College, National Cheng Kung University, Tainan, Taiwan

关键词: Pathogenesis;    Hemorrhage;    Permeability;    Endothelium;   

Others  :  823786
DOI  :  10.1186/1423-0127-20-42

 received in 2013-03-23, accepted in 2013-06-18,  发布年份 2013

【 摘 要 】

Dengue virus (DENV) infection can cause life-threatening dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Vascular leakage and abnormal hemorrhage are the two major pathogenic changes found in these patients. From previous studies, it is known that both antibodies and cytokines induced in response to DENV infection are involved in the immunopathogenesis of DHF/DSS. However, the role of viral factors during DENV infection remains unclear. Nonstructural protein 1 (NS1), which is secreted in the sera of patients, is a useful diagnostic marker for acute DENV infection. Nevertheless, the roles of NS1 and its antibodies in the pathogenesis of DHF/DSS are unclear. The focus of this review is to evaluate the possible contributions of NS1 and the antibodies it induces to vascular leakage and abnormal hemorrhage during DENV infection, which may provide clues to better understanding the pathogenesis of DHF/DSS.

【 授权许可】

   
2013 Chuang et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Gubler DJ: Dengue/dengue haemorrhagic fever: history and current status. Novartis Found Symp 2006, 277:3-16. discussion 16–22, 71–73, 251–253
• [2]Henchal EA, Putnak JR: The dengue viruses. Clin Microbiol Rev 1990, 3:376-396.
• [3]Guzman MG, Halstead SB, Artsob H, Buchy P, Farrar J, Gubler DJ, Hunsperger E, Kroeger A, Margolis HS, Martinez E, et al.: Dengue: a continuing global threat. Nat Rev Microbiol 2010, 8:S7-S16.
• [4]Pinheiro FP, Corber SJ: Global situation of dengue and dengue haemorrhagic fever, and its emergence in the Americas. World Health Stat Q 1997, 50:161-169.
• [5]Kyle JL, Harris E: Global spread and persistence of dengue. Annu Rev Microbiol 2008, 62:71-92.
• [6]Guzman MG, Kouri G: Dengue: an update. Lancet Infect Dis 2002, 2:33-42.
• [7]Simmons CP, Farrar JJ, Nguyen vV, Wills B: Dengue. N Engl J Med 2012, 366:1423-1432.
• [8]Vaughn DW, Green S, Kalayanarooj S, Innis BL, Nimmannitya S, Suntayakorn S, Endy TP, Raengsakulrach B, Rothman AL, Ennis FA, Nisalak A: Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity. J Infect Dis 2000, 181:2-9.
• [9]Ngo NT, Cao XT, Kneen R, Wills B, Nguyen VM, Nguyen TQ, Chu VT, Nguyen TT, Simpson JA, Solomon T, et al.: Acute management of dengue shock syndrome: a randomized double-blind comparison of 4 intravenous fluid regimens in the first hour. Clin Infect Dis 2001, 32:204-213.
• [10]Halstead SB: Dengue vaccine development: a 75% solution? Lancet 2012, 380:1535-1536.
• [11]Herrero LJ, Zakhary A, Gahan ME, Nelson MA, Herring BL, Hapel AJ, Keller PA, Obeysekera M, Chen W, Sheng KC, et al.: Dengue virus therapeutic intervention strategies based on viral, vector and host factors involved in disease pathogenesis. Pharmacol Ther 2013, 137:266-282.
• [12]Whitehorn J, Farrar J: Dengue. Br Med Bull 2010, 95:161-173.
• [13]Muller DA, Young PR: The flavivirus NS1 protein: molecular and structural biology, immunology, role in pathogenesis and application as a diagnostic biomarker. Antiviral Res 2013, 98:192-208.
• [14]Jacobs MG, Robinson PJ, Bletchly C, Mackenzie JM, Young PR: Dengue virus nonstructural protein 1 is expressed in a glycosyl-phosphatidylinositol-linked form that is capable of signal transduction. FASEB J 2000, 14:1603-1610.
• [15]Wallis TP, Huang CY, Nimkar SB, Young PR, Gorman JJ: Determination of the disulfide bond arrangement of dengue virus NS1 protein. J Biol Chem 2004, 279:20729-20741.
• [16]Gutsche I, Coulibaly F, Voss JE, Salmon J, d’Alayer J, Ermonval M, Larquet E, Charneau P, Krey T, Megret F, et al.: Secreted dengue virus nonstructural protein NS1 is an atypical barrel-shaped high-density lipoprotein. Proc Natl Acad Sci USA 2011, 108:8003-8008.
• [17]Flamand M, Megret F, Mathieu M, Lepault J, Rey FA, Deubel V: Dengue virus type 1 nonstructural glycoprotein NS1 is secreted from mammalian cells as a soluble hexamer in a glycosylation-dependent fashion. J Virol 1999, 73:6104-6110.
• [18]Alcon S, Talarmin A, Debruyne M, Falconar A, Deubel V, Flamand M: 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 2002, 40:376-381.
• [19]Libraty DH, Young PR, Pickering D, Endy TP, Kalayanarooj S, Green S, Vaughn DW, Nisalak A, Ennis FA, Rothman AL: 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 2002, 186:1165-1168.
• [20]Young PR, Hilditch PA, Bletchly C, Halloran W: 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 2000, 38:1053-1057.
• [21]Peeling RW, Artsob H, Pelegrino JL, Buchy P, Cardosa MJ, Devi S, Enria DA, Farrar J, Gubler DJ, Guzman MG, et al.: Evaluation of diagnostic tests: dengue. Nat Rev Microbiol 2010, 8:S30-S38.
• [22]Adamczak R, Porollo A, Meller J: Combining prediction of secondary structure and solvent accessibility in proteins. Proteins 2005, 59:467-475.
• [23]Khromykh AA, Sedlak PL, Westaway EG: cis- and trans-acting elements in flavivirus RNA replication. J Virol 2000, 74:3253-3263.
• [24]Mackenzie JM, Jones MK, Young PR: Immunolocalization of the dengue virus nonstructural glycoprotein NS1 suggests a role in viral RNA replication. Virology 1996, 220:232-240.
• [25]Kurosu T, Chaichana P, Yamate M, Anantapreecha S, Ikuta K: Secreted complement regulatory protein clusterin interacts with dengue virus nonstructural protein 1. Biochem Biophys Res Commun 2007, 362:1051-1056.
• [26]Avirutnan P, Punyadee N, Noisakran S, Komoltri C, Thiemmeca S, Auethavornanan K, Jairungsri A, Kanlaya R, Tangthawornchaikul N, Puttikhunt C, et al.: Vascular leakage in severe dengue virus infections: a potential role for the nonstructural viral protein NS1 and complement. J Infect Dis 2006, 193:1078-1088.
• [27]Whitehorn J, Simmons CP: The pathogenesis of dengue. Vaccine 2011, 29:7221-7228.
• [28]Lin CF, Wan SW, Cheng HJ, Lei HY, Lin YS: Autoimmune pathogenesis in dengue virus infection. Viral Immunol 2006, 19:127-132.
• [29]Wan SW, Lin CF, Yeh TM, Liu CC, Liu HS, Wang S, Ling P, Anderson R, Lei HY, Lin YS: Autoimmunity in dengue pathogenesis. J Formos Med Assoc 2013, 112:3-11.
• [30]Srikiatkhachorn A: Plasma leakage in dengue haemorrhagic fever. Thromb Haemostasis 2009, 102:1042-1049.
• [31]Trung DT, Wills B: Systemic vascular leakage associated with dengue infections - the clinical perspective. Curr Top Microbiol Immunol 2010, 338:57-66.
• [32]Lin SW, Chuang YC, Lin YS, Lei HY, Liu HS, Yeh TM: Dengue virus nonstructural protein NS1 binds to prothrombin/thrombin and inhibits prothrombin activation. J Infect 2012, 64:325-334.
• [33]Chuang YC, Lei HY, Liu HS, Lin YS, Fu TF, Yeh TM: Macrophage migration inhibitory factor induced by dengue virus infection increases vascular permeability. Cytokine 2011, 54:222-231.
• [34]Ait-Oufella H, Maury E, Lehoux S, Guidet B, Offenstadt G: The endothelium: physiological functions and role in microcirculatory failure during severe sepsis. Intens Care Med 2010, 36:1286-1298.
• [35]Komarova Y, Malik AB: Regulation of endothelial permeability via paracellular and transcellular transport pathways. Annu Rev Physiol 2010, 72:463-493.
• [36]Schmidt EP, Yang Y, Janssen WJ, Gandjeva A, Perez MJ, Barthel L, Zemans RL, Bowman JC, Koyanagi DE, Yunt ZX, et al.: The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. Nat Med 2012, 18:1217-1223.
• [37]Curry FR, Noll T: Spotlight on microvascular permeability. Cardiovasc Res 2010, 87:195-197.
• [38]Sahaphong S, Riengrojpitak S, Bhamarapravati N, Chirachariyavej T: Electron microscopic study of the vascular endothelial cell in dengue hemorrhagic fever. Southeast Asian J Trop Med Public Health 1980, 11:194-204.
• [39]Sosothikul D, Seksarn P, Pongsewalak S, Thisyakorn U, Lusher J: Activation of endothelial cells, coagulation and fibrinolysis in children with Dengue virus infection. Thromb Haemostasis 2007, 97:627-634.
• [40]Huang YH, Lei HY, Liu HS, Lin YS, Liu CC, Yeh TM: Dengue virus infects human endothelial cells and induces IL-6 and IL-8 production. Am J Trop Med Hyg 2000, 63:71-75.
• [41]Halstead SB: Pathogenesis of dengue: challenges to molecular biology. Science 1988, 239:476-481.
• [42]Jessie K, Fong MY, Devi S, Lam SK, Wong KT: Localization of dengue virus in naturally infected human tissues, by immunohistochemistry and in situ hybridization. J Infect Dis 2004, 189:1411-1418.
• [43]Appanna R, Wang SM, Ponnampalavanar SA, Lum LC, Sekaran SD: Cytokine factors present in dengue patient sera induces alterations of junctional proteins in human endothelial cells. Am J Trop Med Hyg 2012, 87:936-942.
• [44]Ong SP, Lee LM, Leong YF, Ng ML, Chu JJ: Dengue virus infection mediates HMGB1 release from monocytes involving PCAF acetylase complex and induces vascular leakage in endothelial cells. PLoS One 2012, 7:e41932.
• [45]Dewi BE, Takasaki T, Kurane I: In vitro assessment of human endothelial cell permeability: effects of inflammatory cytokines and dengue virus infection. J Virol Methods 2004, 121:171-180.
• [46]Lee YR, Liu MT, Lei HY, Liu CC, Wu JM, Tung YC, Lin YS, Yeh TM, Chen SH, Liu HS: 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 2006, 87:3623-3630.
• [47]Assuncao-Miranda I, Amaral FA, Bozza FA, Fagundes CT, Sousa LP, Souza DG, Pacheco P, Barbosa-Lima G, Gomes RN, Bozza PT, et al.: Contribution of macrophage migration inhibitory factor to the pathogenesis of dengue virus infection. FASEB J 2010, 24:218-228.
• [48]Souza DG, Fagundes CT, Sousa LP, Amaral FA, Souza RS, Souza AL, Kroon EG, Sachs D, Cunha FQ, Bukin E, et al.: Essential role of platelet-activating factor receptor in the pathogenesis of Dengue virus infection. Proc Natl Acad Sci USA 2009, 106:14138-14143.
• [49]Halstead SB: Dengue: hematologic aspects. Semin Hematol 1982, 19:116-131.
• [50]Halstead SB: Antibody, macrophages, dengue virus infection, shock, and hemorrhage: a pathogenetic cascade. Rev Infect Dis 1989, 11(Suppl 4):S830-S839.
• [51]La Russa VF, Innis BL: Mechanisms of dengue virus-induced bone marrow suppression. Baillieres Clin Haematol 1995, 8:249-270.
• [52]Lei HY, Yeh TM, Liu HS, Lin YS, Chen SH, Liu CC: Immunopathogenesis of dengue virus infection. J Biomed Sci 2001, 8:377-388.
• [53]Mitrakul C, Poshyachinda M, Futrakul P, Sangkawibha N, Ahandrik S: Hemostatic and platelet kinetic studies in dengue hemorrhagic fever. Am J Trop Med Hyg 1977, 26:975-984.
• [54]Phanichyakarn P, Israngkura PB, Krisarin C, Pongpanich B, Dhanamitta S, Valyasevi A, Studies on dengue hemorrhagic fever. IV: Fluorescence staining of the immune complexes on platelets. J Med Assoc Thai 1977, 60:307-311.
• [55]Lin CF, Lei HY, Liu CC, Liu HS, Yeh TM, Wang ST, Yang TI, Sheu FC, Kuo CF, Lin YS: Generation of IgM anti-platelet autoantibody in dengue patients. J Med Virol 2001, 63:143-149.
• [56]Sun DS, King CC, Huang HS, Shih YL, Lee CC, Tsai WJ, Yu CC, Chang HH: Antiplatelet autoantibodies elicited by dengue virus non-structural protein 1 cause thrombocytopenia and mortality in mice. J Thromb Haemost 2007, 5:2291-2299.
• [57]Wills BA, Oragui EE, Stephens AC, Daramola OA, Dung NM, Loan HT, Chau NV, Chambers M, Stepniewska K, Farrar JJ, Levin M: Coagulation abnormalities in dengue hemorrhagic fever: serial investigations in 167 Vietnamese children with dengue shock syndrome. Clin Infect Dis 2002, 35:277-285.
• [58]Mairuhu AT, Mac Gillavry MR, Setiati TE, Soemantri A, ten Cate H, Brandjes DP, van Gorp EC: Is clinical outcome of dengue-virus infections influenced by coagulation and fibrinolysis? A critical review of the evidence. Lancet Infect Dis 2003, 3:33-41.
• [59]Krishnamurti C, Kalayanarooj S, Cutting MA, Peat RA, Rothwell SW, Reid TJ, Green S, Nisalak A, Endy TP, Vaughn DW, et al.: Mechanisms of hemorrhage in dengue without circulatory collapse. Am J Trop Med Hyg 2001, 65:840-847.
• [60]Huang YH, Liu CC, Wang ST, Lei HY, Liu HL, Lin YS, Wu HL, Yeh TM: Activation of coagulation and fibrinolysis during dengue virus infection. J Med Virol 2001, 63:247-251.
• [61]Chuang YC, Lin YS, Liu CC, Liu HS, Liao SH, Shi MD, Lei HY, Yeh TM: Factors contributing to the disturbance of coagulation and fibrinolysis in dengue virus infection. J Formos Med Assoc 2013, 112:12-17.
• [62]Dejnirattisai W, Jumnainsong A, Onsirisakul N, Fitton P, Vasanawathana S, Limpitikul W, Puttikhunt C, Edwards C, Duangchinda T, Supasa S, et al.: Cross-reacting antibodies enhance dengue virus infection in humans. Science 2010, 328:745-748.
• [63]Falconar AK: 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 1997, 142:897-916.
• [64]Lin CF, Lei HY, Shiau AL, Liu HS, Yeh TM, Chen SH, Liu CC, Chiu SC, Lin YS: Endothelial cell apoptosis induced by antibodies against dengue virus nonstructural protein 1 via production of nitric oxide. J Immunol 2002, 169:657-664.
• [65]Cheng HJ, Lei HY, Lin CF, Luo YH, Wan SW, Liu HS, Yeh TM, Lin YS: Anti-dengue virus nonstructural protein 1 antibodies recognize protein disulfide isomerase on platelets and inhibit platelet aggregation. Mol Immunol 2009, 47:398-406.
• [66]Chuang YC, Lin YS, Liu HS, Wang JR, Yeh TM: Antibodies against thrombin in dengue patients contain both anti-thrombotic and pro-fibrinolytic activities. Thromb Haemost 2013., 110in press
• [67]Chuang YC, Lei HY, Lin YS, Liu HS, Wu HL, Yeh TM: Dengue virus-induced autoantibodies bind to plasminogen and enhance its activation. J Immunol 2011, 187:6483-6490.
• [68]Lin CF, Lei HY, Shiau AL, Liu CC, Liu HS, Yeh TM, Chen SH, Lin YS: Antibodies from dengue patient sera cross-react with endothelial cells and induce damage. J Med Virol 2003, 69:82-90.
• [69]Huang KJ, Li SYJ, Chen SC, Liu HS, Lin YS, Yeh TM, Liu CC, Lei HY: Manifestation of thrombocytopenia in dengue-2-virus-infected mice. J Gen Virol 2000, 81:2177-2182.
• [70]Lin YS, Yeh TM, Lin CF, Wan SW, Chuang YC, Hsu TK, Liu HS, Liu CC, Anderson R, Lei HY: Molecular mimicry between virus and host and its implications for dengue disease pathogenesis. Exp Biol Med (Maywood) 2011, 236:515-523.
• [71]Wills B, Tran VN, Nguyen TH, Truong TT, Tran TN, Nguyen MD, Tran VD, Nguyen VV, Dinh TT, Farrar J: Hemostatic changes in Vietnamese children with mild dengue correlate with the severity of vascular leakage rather than bleeding. Am J Trop Med Hyg 2009, 81:638-644.
• [72]Avirutnan P, Zhang L, Punyadee N, Manuyakorn A, Puttikhunt C, Kasinrerk W, Malasit P, Atkinson JP, Diamond MS: Secreted NS1 of dengue virus attaches to the surface of cells via interactions with heparan sulfate and chondroitin sulfate E. PLoS Pathog 2007, 3:e183.
• [73]Alcon-LePoder S, Drouet MT, Roux P, Frenkiel MP, Arborio M, Durand-Schneider AM, Maurice M, Le Blanc I, Gruenberg J, Flamand M: The secreted form of dengue virus nonstructural protein NS1 is endocytosed by hepatocytes and accumulates in late endosomes: implications for viral infectivity. J Virol 2005, 79:11403-11411.
• [74]Avirutnan P, Fuchs A, Hauhart RE, Somnuke P, Youn S, Diamond MS, Atkinson JP: Antagonism of the complement component C4 by flavivirus nonstructural protein NS1. J Exp Med 2010, 207:793-806.
• [75]Avirutnan P, Hauhart RE, Somnuke P, Blom AM, Diamond MS, Atkinson JP: Binding of flavivirus nonstructural protein NS1 to C4b binding protein modulates complement activation. J Immunol 2011, 187:424-433.
• [76]Watanabe S, Tan KH, Rathore AP, Rozen-Gagnon K, Shuai W, Ruedl C, Vasudevan SG: The magnitude of dengue virus NS1 protein secretion is strain dependent and does not correlate with severe pathologies in the mouse infection model. J Virol 2012, 86:5508-5514.
• [77]Lee WL, Slutsky AS: Sepsis and endothelial permeability. N Engl J Med 2010, 363:689-691.
• [78]Halstead SB: Dengue vascular permeability syndrome: what, no T cells? Clin Infect Dis 2013, 56:900-901.