Deletion of the C-terminal region of dengue virus nonstructural protein 1 (NS1) abolishes anti-NS1-mediated platelet dysfunction and bleeding tendency.
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 DeltaC NS1). Anti-DeltaC NS1 Abs exhibited lower platelet binding activity than that of anti-full-length NS1. Anti-full-length NS1 but not anti-DeltaC NS1 Abs inhibited platelet aggregation, which was shown to involve integrin alpha(IIb)beta(3) inactivation. We found that the bleeding time in full-length NS1-hyperimmunized mice was longer than that in the normal control mice. By contrast, DeltaC NS1-hyperimmunized mice showed a bleeding time similar to that of normal control mice. Passively administered anti-DV NS1, but not anti-DeltaC 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-DeltaC NS1, Ab administration. In summary, platelet dysfunction and bleeding tendency are induced by anti-full-length DV NS1 but not by anti-DeltaC NS1 Abs. These findings may be important not only for understanding dengue hemorrhagic disease pathogenesis but also for dengue vaccine development.
Chen
Mei-Chun
MC
Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan.
Lin
Chiou-Feng
CF
Lei
Huan-Yao
HY
Lin
Shih-Chao
SC
Liu
Hsiao-Sheng
HS
Yeh
Trai-Ming
TM
Anderson
Robert
R
Lin
Yee-Shin
YS
D000818:Animals; D000914:Antibodies, Viral; D000956:Antigens, Viral; D001791:Blood Platelet Disorders / Q000209:etiology / Q000276:immunology* / Q000821:virology; D001792:Blood Platelets / Q000276:immunology / Q000473:pathology / Q000821:virology; D003429:Cross Reactions / Q000276:immunology; D003716:Dengue Virus / Q000737:chemistry / Q000276:immunology*; D006470:Hemorrhage / Q000209:etiology / Q000276:immunology / Q000821:virology; D006801:Humans; D051379:Mice; D017384:Sequence Deletion; D019595:Severe Dengue / Q000276:immunology* / Q000821:virology; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000276:immunology*
D000914:Antibodies, Viral; D000956:Antigens, Viral; D017361:Viral Nonstructural Proteins