Abstract
Thrombocytopenia is a clinical manifestation in dengue virus (DV) infection, yet its pathogenic mechanisms are unresolved. We previously showed that dengue patient sera contained antibodies cross-reactive with platelets. In this study, we demonstrated that the anti-platelet activity of dengue patient sera was due to the antibodies against DV nonstructural protein 1 (NS1). Studies using DV-infected or recombinant NS1-immunized mouse sera showed that anti-NS1 antibodies cross-reacted with human platelets. The platelet-binding activity of dengue patient sera or anti-NS1 antibodies was inhibited by treatment of platelets with anti-NS1 or patient sera. Further investigation showed that anti-NS1 antibodies were able to inhibit platelet aggregation and cause platelet lysis in the presence of complement. The platelet-binding activity and the induction of platelet lysis mediated by dengue patient sera or anti-NS1 antibodies were increased when platelets were activated by ADP or thrombin. Taken together, anti-NS1 antibodies account for the cross-reactivity with platelets and cause platelet dysfunction or depletion, which may be involved in the pathogenesis of dengue diseases.
Highlights
Dengue virus (DV), an important human pathogenic flavivirus, causes serious epidemic disease[1]
To further investigate the binding activity of anti-nonstructural protein 1 (NS1) antibodies to platelets, human platelets were preabsorbed with anti-NS1 IgG or patient sera to block the potential cross-reactive molecules on the surface of platelets
We showed that anti-NS1 antibodies, at least in part, account for the platelet-binding ability of dengue patient sera
Summary
Dengue virus (DV), an important human pathogenic flavivirus, causes serious epidemic disease[1]. In addition to the direct cell damage caused by virus-specified factors, host immune responses to virus infection may contribute to the severity of dengue disease. The onset of autoimmune responses to DV infection may contribute to dengue disease pathogenesis[10,19,20,21]. The presence of cross-reactive antibodies in dengue patient sera causing platelet lysis provide a potential mechanism for platelet loss[28]. The manifestation of thrombocytopenia and the generation of anti-platelet antibody in DV-infected mice provide a model for the pathogenicity of dengue disease[29]. Our previous studies[28] demonstrated that antibodies reactive with platelets were present in dengue patient sera. We demonstrate that anti-NS1 antibodies account for the cross-reactivity of patient sera with platelets. We show further that anti-NS1 antibodies generated in mice exhibit binding activity with human platelets and that anti-NS1 antibodies have effects on platelet aggregation and platelet lysis
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