The Dual Role of the Antibody Response Against the Flavivirus Non-structural Protein 1 (NS1) in Protection and Immuno-Pathogenesis

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2019 Aug 6

PMID 31379848

Citations 24

Authors

Arturo Reyes-Sandoval

Juan E Ludert

Affiliations

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Abstract

Dengue and Zika viruses are closely related mosquito-borne flaviviruses responsible for major public health problems in tropical and sub-tropical countries. The genomes of both, dengue and zika viruses encodes 10 genes that are translated into three structural proteins (C, prM, and E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). The non-structural protein 1 (NS1) is a highly conserved glycoprotein of approximately 48-50 KDa. In infected cells, NS1 is found as a homodimer associated with intracellular membranes and replication complexes, serving as a scaffolding protein in virus replication and morphogenesis. NS1 is secreted efficiently from infected cells as a hexamer and is found in patient's sera during the acute phase of the disease. NS1 detection in sera is a valuable diagnostic marker and immunization with NS1 has been shown to protect animal models from lethal challenges with dengue and Zika viruses. Nevertheless, soluble NS1 has been associated with severe dengue and anti-NS1 antibodies have been reported to cross-react with host platelets and endothelial cells and thus presumably contribute to pathogenesis. Due to the implications of NS1 in arbovirus pathogenesis and its relevance as vaccine candidate, we discuss the dual role that anti-NS1 antibodies may play in protection and disease and the challenges that need to be overcome to develop safe and effective NS1-based vaccines against dengue and Zika.

Citing Articles

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References

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(2):376-81. PMC: 153354. DOI: 10.1128/JCM.40.02.376-381.2002. View

Lin C, Lei H, Shiau A, Liu H, Yeh T, Chen S . Endothelial cell apoptosis induced by antibodies against dengue virus nonstructural protein 1 via production of nitric oxide. J Immunol. 2002; 169(2):657-64. DOI: 10.4049/jimmunol.169.2.657. View

Libraty D, Young P, Pickering D, Endy T, Kalayanarooj S, Green S . 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(8):1165-8. DOI: 10.1086/343813. View

Lin C, Lei H, Shiau A, Liu C, Liu H, Yeh T . Antibodies from dengue patient sera cross-react with endothelial cells and induce damage. J Med Virol. 2002; 69(1):82-90. DOI: 10.1002/jmv.10261. View

Wu S, Liao C, Lin Y, Yeh C, Chen L, Huang Y . Evaluation of protective efficacy and immune mechanisms of using a non-structural protein NS1 in DNA vaccine against dengue 2 virus in mice. Vaccine. 2003; 21(25-26):3919-29. DOI: 10.1016/s0264-410x(03)00310-4. View

Lin C, Chiu S, Hsiao Y, Wan S, Lei H, Shiau A . Expression of cytokine, chemokine, and adhesion molecules during endothelial cell activation induced by antibodies against dengue virus nonstructural protein 1. J Immunol. 2004; 174(1):395-403. DOI: 10.4049/jimmunol.174.1.395. View

Costa S, Freire M, Alves A . DNA vaccine against the non-structural 1 protein (NS1) of dengue 2 virus. Vaccine. 2005; 24(21):4562-4. DOI: 10.1016/j.vaccine.2005.08.022. View

Avirutnan P, Punyadee N, Noisakran S, Komoltri C, Thiemmeca S, Auethavornanan K . Vascular leakage in severe dengue virus infections: a potential role for the nonstructural viral protein NS1 and complement. J Infect Dis. 2006; 193(8):1078-88. DOI: 10.1086/500949. View

Clyde K, Kyle J, Harris E . Recent advances in deciphering viral and host determinants of dengue virus replication and pathogenesis. J Virol. 2006; 80(23):11418-31. PMC: 1642597. DOI: 10.1128/JVI.01257-06. View

10.

Costa S, Azevedo A, Paes M, Sarges F, Freire M, Alves A . DNA vaccines against dengue virus based on the ns1 gene: the influence of different signal sequences on the protein expression and its correlation to the immune response elicited in mice. Virology. 2006; 358(2):413-23. DOI: 10.1016/j.virol.2006.08.052. View

11.

Alcon-LePoder S, Sivard P, Drouet M, Talarmin A, Rice C, Flamand M . Secretion of flaviviral non-structural protein NS1: from diagnosis to pathogenesis. Novartis Found Symp. 2007; 277:233-47. DOI: 10.1002/0470058005.ch17. View

12.

Lin C, Wan S, Chen M, Lin S, Cheng C, Chiu S . Liver injury caused by antibodies against dengue virus nonstructural protein 1 in a murine model. Lab Invest. 2008; 88(10):1079-89. DOI: 10.1038/labinvest.2008.70. View

13.

Chen M, Lin C, Lei H, Lin S, Liu H, Yeh T . Deletion of the C-terminal region of dengue virus nonstructural protein 1 (NS1) abolishes anti-NS1-mediated platelet dysfunction and bleeding tendency. J Immunol. 2009; 183(3):1797-803. DOI: 10.4049/jimmunol.0800672. View

14.

Cheng H, Lei H, Lin C, Luo Y, Wan S, Liu H . Anti-dengue virus nonstructural protein 1 antibodies recognize protein disulfide isomerase on platelets and inhibit platelet aggregation. Mol Immunol. 2009; 47(2-3):398-406. DOI: 10.1016/j.molimm.2009.08.033. View

15.

Liu I, Chiu C, Chen Y, Wu H . Molecular mimicry of human endothelial cell antigen by autoantibodies to nonstructural protein 1 of dengue virus. J Biol Chem. 2011; 286(11):9726-36. PMC: 3058979. DOI: 10.1074/jbc.M110.170993. View

16.

Falgout B, Bray M, Schlesinger J, Lai C . Immunization of mice with recombinant vaccinia virus expressing authentic dengue virus nonstructural protein NS1 protects against lethal dengue virus encephalitis. J Virol. 1990; 64(9):4356-63. PMC: 247903. DOI: 10.1128/JVI.64.9.4356-4363.1990. View

17.

Gutsche I, Coulibaly F, Voss J, Salmon J, dAlayer J, Ermonval M . Secreted dengue virus nonstructural protein NS1 is an atypical barrel-shaped high-density lipoprotein. Proc Natl Acad Sci U S A. 2011; 108(19):8003-8. PMC: 3093454. DOI: 10.1073/pnas.1017338108. View

18.

Whitehorn J, Simmons C . The pathogenesis of dengue. Vaccine. 2011; 29(42):7221-8. DOI: 10.1016/j.vaccine.2011.07.022. View

19.

Lin S, Chuang Y, Lin Y, Lei H, Liu H, Yeh T . Dengue virus nonstructural protein NS1 binds to prothrombin/thrombin and inhibits prothrombin activation. J Infect. 2011; 64(3):325-34. DOI: 10.1016/j.jinf.2011.11.023. View

20.

Amorim J, Diniz M, Cariri F, Rodrigues J, Bizerra R, Goncalves A . Protective immunity to DENV2 after immunization with a recombinant NS1 protein using a genetically detoxified heat-labile toxin as an adjuvant. Vaccine. 2011; 30(5):837-45. DOI: 10.1016/j.vaccine.2011.12.034. View