Volume 24 Issue 3 - June 21, 2013 PDF
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Deletion of the C-Terminal Region of Dengue Virus Nonstructural Protein 1 (NS1) Abolishes Anti-NS1-Mediated Platelet Dysfunction and Bleeding Tendency
Mei-Chun Chen1, Chiou-Feng Lin2, Huan-Yao Lei1, Shih-Chao Lin,1 Hsiao-Sheng Liu1, Trai-Ming Yeh3, Robert Anderson4, Yee-Shin Lin1,5,*
1Department of Microbiology and Immunology,
2Institute of Clinical Medicine,
3Department of Medical Laboratory Science and Biotechnology, 
5Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University Medical
College, Tainan, Taiwan; 
4Department of Microbiology and Immunology,Dalhousie University, Halifax, Nova Scotia, Canada
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Infection with dengue viruses (DV) causes disease ranging from mild dengue fever to severe dengue hemorrhagic fever and dengue shock syndrome. The clinical features include plasma leakage, bleeding tendency, and thrombocytopenia. The mechanisms underlying dengue hemorrhagic disease are incompletely understood. We previously showed that anti-DV nonstructural protein 1 (NS1) antibodies cross-react with human platelets and inhibit platelet aggregation. Based on sequence homology alignment, the major cross-reactive epitopes reside in the C-terminal region of DV NS1. In this study, we compared the effects of antibodies against full-length DV NS1 and NS1 lacking the C-terminal amino acid residues 271 to 352 (designated ΔC NS1). Anti-ΔC NS1 antibodies exhibited lower platelet binding activity than that of anti-full-length DV NS1 (Figure 1). Anti-full-length NS1 but not anti-ΔC NS1 antibodies inhibited platelet aggregation (Figure 2), which was shown to involve integrin αIIbβ3 inactivation (Figure 3). Mouse tail bleeding time in full-length NS1-hyperimmunized mice was longer than that in the normal control mice. By contrast, ΔC NS1-hyperimmunized mice showed a bleeding time similar to that of normal control mice (Figure 4). Passively administered anti-full-length DV NS1, but not anti-ΔC NS1, antibody level decreased markedly in serum and this decrease was correlated with antibody binding to platelets. A transient platelet loss in the circulation was observed after anti-full-length DV NS1, but not anti-ΔC NS1, antibody administration. In summary, platelet dysfunction and bleeding tendency are induced by anti-full-length DV NS1 but not by anti-ΔC NS1 antibodies. These findings give an insight into dengue disease pathogenesis as well as dengue vaccine strategies.
Fig. 3. Anti-full-length DV NS1 but not anti-ΔC NS1 antibodies inhibit ADP-induced integrin αIIbβ3 activation in platelets. (Source: Chen, M. C. et al. J. Immunol. 183, 1797-1803, 2009)
Fig. 1. Anti-ΔC NS1 antibodies show lower binding to human platelets than that of anti-full-length DV NS1 antibodies. (Source: Chen, M. C. et al. J. Immunol. 183, 1797-1803, 2009)

Fig. 4. Prolonged bleeding time in full-length DV NS1- but not ΔC NS1-hyperimmunized mice. (Source: Chen, M. C. et al. J. Immunol. 183, 1797-1803, 2009)
Fig. 2. Anti-full-length DV NS1 but not anti-ΔC NS1 antibodies inhibit ADP-induced platelet aggregation. (Source: Chen, M. C. et al. J. Immunol. 183, 1797-1803, 2009)
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