title: Anti-dengue virus nonstructural protein 1 antibodies recognize protein disulfide isomerase on platelets and inhibit platelet aggregation.
abstract: Hemorrhagic syndrome is a hallmark of severe dengue diseases. We previously suggested a mechanism of molecular mimicry in which antibodies against dengue virus (DV) nonstructural protein 1 (NS1) cross-react with platelets. In the present study, we demonstrate that protein disulfide isomerase (PDI) on the platelet surface is recognized by anti-DV NS1 antibodies. Anti-DV NS1 obtained from hyperimmunized mouse sera inhibited PDI activity and platelet aggregation, and both inhibitory effects were prevented when anti-DV NS1 antibodies were preabsorbed with PDI. Anti-PDI antibodies bound to a peptide consisting of amino acid residues 311-330 (P311-330) of NS1. This peptide was a predicted epitope analyzed by homologous sequence alignments between DV NS1 and PDI. The platelet binding activities of anti-PDI and anti-DV NS1 antibodies were both reduced by P311-330 preabsorption. Similar to the findings using anti-DV NS1, antibodies against P311-330 bound to PDI and platelets, followed by inhibition of PDI activity and platelet aggregation. Furthermore, the cross-reactivity of dengue hemorrhagic fever patient sera with platelets was reduced when patient sera were preabsorbed with PDI or P311-330. Dengue hemorrhagic fever patient sera also inhibited platelet aggregation, while PDI or P311-330 reduced this inhibitory effect. In conclusion, anti-DV NS1 antibodies cross-react with PDI on platelet surface causing inhibition of platelet aggregation, which may provide implications in dengue disease pathogenesis.
authors.affiliation: Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan.
authors.forename: Hsien-Jen
authors.initials: HJ
authors.lastname: Cheng
authors.forename: Huan-Yao
authors.initials: HY
authors.lastname: Lei
authors.forename: Chiou-Feng
authors.initials: CF
authors.lastname: Lin
authors.forename: Yueh-Hsia
authors.initials: YH
authors.lastname: Luo
authors.forename: Shu-Wen
authors.initials: SW
authors.lastname: Wan
authors.forename: Hsiao-Sheng
authors.initials: HS
authors.lastname: Liu
authors.forename: Trai-Ming
authors.initials: TM
authors.lastname: Yeh
authors.forename: Yee-Shin
authors.initials: YS
authors.lastname: Lin
mesh_terms: D000042:Absorption; D000595:Amino Acid Sequence; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology*; D001792:Blood Platelets / Q000201:enzymology* / Q000276:immunology*; D002457:Cell Extracts / Q000276:immunology; D003429:Cross Reactions / Q000276:immunology; D003716:Dengue Virus / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D010974:Platelet Aggregation / Q000276:immunology*; D019704:Protein Disulfide-Isomerases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000276:immunology*; D019595:Severe Dengue / Q000276:immunology / Q000821:virology; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D002457:Cell Extracts; D000939:Epitopes; C079340:NS1 protein, Dengue virus type 2; D010455:Peptides; D017361:Viral Nonstructural Proteins; D019704:Protein Disulfide-Isomerases