HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0800672v1 183/3/1797    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Chen, M.-C. Articles by Lin, Y.-S. PubMed PubMed Citation Articles by Chen, M.-C. Articles by Lin, Y.-S.

Deletion of the C-Terminal Region of Dengue Virus Nonstructural Protein 1 (NS1) Abolishes Anti-NS1-Mediated Platelet Dysfunction and Bleeding Tendency¹

Mei-Chun Chen^*, Chiou-Feng Lin, Huan-Yao Lei^*, Shih-Chao Lin^*, Hsiao-Sheng Liu^*, Trai-Ming Yeh, Robert Anderson^¶ and Yee-Shin Lin^2,*,

^* Department of Microbiology and Immunology, Institute of Clinical Medicine, Department of Medical Laboratory Science and Biotechnology, and Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University Medical College, Tainan, Taiwan; and ^¶ Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada

The mechanisms underlying dengue hemorrhagic disease are incompletely understood. We previously showed that anti-dengue virus (DV) nonstructural protein 1 (NS1) Abs cross-react with human platelets and inhibit platelet aggregation. Based on sequence homology alignment, the cross-reactive epitopes reside in the C-terminal region of DV NS1. In this study, we compared the effects of Abs against full-length DV NS1 and NS1 lacking the C-terminal aa 271 to 352 (designated C NS1). Anti-C NS1 Abs exhibited lower platelet binding activity than that of anti-full-length NS1. Anti-full-length NS1 but not anti-C NS1 Abs inhibited platelet aggregation, which was shown to involve integrin _IIbβ₃ inactivation. We found that the bleeding time in full-length NS1-hyperimmunized mice was longer than that in the normal control mice. By contrast, C NS1-hyperimmunized mice showed a bleeding time similar to that of normal control mice. Passively administered anti-DV NS1, but not anti-C NS1, Ab level decreased markedly in serum and this decrease was correlated with Ab binding to platelets. A transient platelet loss in the circulation was observed after anti-DV NS1, but not anti-C NS1, Ab administration. In summary, platelet dysfunction and bleeding tendency are induced by anti-full-length DV NS1 but not by anti-C NS1 Abs. These findings may be important not only for understanding dengue hemorrhagic disease pathogenesis but also for dengue vaccine development.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant NSC95–3112-B006–002 from the National Research Program for Genomic Medicine, National Science Council, Taiwan.

² Address correspondence and reprint requests to Dr. Yee-Shin Lin, Department of Microbiology and Immunology, National Cheng Kung University Medical College, 1 University Road, Tainan 701, Taiwan. E-mail address: yslin1{at}mail.ncku.edu.tw

³ Abbreviations used in this paper: DV, dengue virus; DHF, dengue hemorrhagic fever; DSS, dengue shock syndrome; NS1, nonstructural protein 1; JEV, Japanese encephalitis virus; PF-4, platelet factor-4; PDI, protein disulfide isomerase.

⁴ The online version of this article contains supplemental material.