C-Terminal Region of Dengue Virus Nonstructural Protein 1 Is Involved in Endothelial Cell Cross-Reactivity via Molecular Mimicry

Mei-Chun Chen,Huan-Yao Lei,Hsiao-Sheng Liu,Shu-Wen Wan,Chiou-Feng Lin,Yee-Shin Lin,Trai-Ming Yeh,Ching-Chuan Liu

doi:10.3844/ajidsp.2008.85.91

Abstract

Infection with dengue virus (DV) causes diseases ranging from self-limited dengue fever to life-threatening dengue hemorrhagic fever and dengue shock syndrome. Vascular leakage, thrombocytopenia and bleeding are the clinical manifestations associated with dengue hemorrhage. We previously showed that anti-DV nonstructural protein 1 (NS1) antibodies (Abs) cross-reacted with endothelial cells. The potential target proteins on endothelial cell surface recognized by anti-DV NS1 Abs showed sequence homology with the C-terminal amino acids (a.a.) 311-352 of DV NS1. In this study, the role of NS1 C-terminal region in dengue autoimmunity was investigated. We deleted the a.a. 277-352 of DV NS1 to prepare truncated NS1 (tNS1) and generated anti-DV tNS1 Abs in mice. The endothelial cell-binding activity of anti-DV tNS1 Abs was lower than that of anti-DV NS1 Abs. In addition, the endothelial cell-binding activity of anti-DV NS1 Abs was inhibited by preabsorption with DV NS1 but not with DV tNS1 proteins. The anti-P311 (a.a. 311-330) and anti-P331 (a.a. 331-350) titers of dengue patient sera were positively correlated with their endothelial cell-binding activity. Dengue patient sera showed lower binding activity to DV tNS1 than to DV NS1 proteins. The endothelial cell-binding activity of dengue patient sera was inhibited by preabsorption with P311 and P331. This study helps to understand the molecular mechanisms of autoimmunity mediated by anti-DV NS1 Abs and to provide the potential implications of tNS1 in dengue vaccine strategies.

Highlights

nonstructural protein 1 (NS1) or recombinant vaccinia virus expressing Dengue virus (DV) NS1 conferred protection in mice[15,16,17]
We previously showed a mechanism of molecular mimicry in which Abs against DV NS1 cross-reacted with endothelial cells and caused damage[21,23]
We further demonstrated that the C-terminal region of DV NS1 plays an important role in endothelial cell cross-reactivity

Summary

Introduction

NS1 or recombinant vaccinia virus expressing DV NS1 conferred protection in mice[15,16,17]. Protection by Dengue virus (DV) belongs to the family. Abs to DV NS1 is thought to involve immune. Flaviviridae and causes mild dengue fever (DF) or severe life-threatening diseases, including dengue recognition of NS1 at the infected cell surface, followed by complement-mediated lysis[16]. DV NS1 hemorrhagic fever (DHF) and dengue shock syndrome (DSS)[1,2,3]. Is expressed in a glycosyl-phosphatidylinositol-linked form with a capacity for signal transduction, as of infection poses a high risk for hemorrhage and shock syndrome, in secondary heterotypic DV infection[4,5,6,7]. Aberrant immune responses to DV evidenced by tyrosine phosphorylation of cellular proteins[18].

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Results

Conclusion