title: Anti-dengue virus nonstructural protein 1 antibodies contribute to platelet phagocytosis by macrophages.
abstract: Thrombocytopenia is an important clinical manifestation of dengue disease. The hypotheses concerning the pathogenesis of thrombocytopenia include decreased production and increased destruction or consumption of platelets. We previously suggested a mechanism of molecular mimicry in which antibodies (Abs) directed against dengue virus (DENV) nonstructural protein 1 (NS1) cross-react with platelets. Furthermore, several lines of evidence show activation of endothelial cells (ECs) and macrophages are related to dengue disease severity. Previous studies also suggested that Ab-opsonised platelets facilitate the engulfment of platelets by macrophages. Here we show that TNF-α-activated ECs upregulate adhesion molecule expression to enhance the binding of platelets and macrophages and lead to anti-DENV NS1 Ab-mediated platelet phagocytosis. We further demonstrate that the interaction between macrophages and TNF-α-activated ECs requires binding of FcγR with the Fc region of platelet-bound anti-DENV NS1 Abs. Importantly, the binding of anti-DENV NS1 Abs to platelets did not interfere with platelet adhesion to ECs. The adhesion molecules ICAM-1 and β3 integrin expressed on ECs as well as the FcγR expressed on macrophages were critical in anti-DENV NS1 Ab-mediated platelet phagocytosis on activated ECs. Moreover, anti-DENV NS1 Abs dramatically enhanced platelet engulfment by macrophages in a murine model of DENV infection. Our study provides evidence for a novel role for anti-DENV NS1 Abs in the pathogenesis of thrombocytopenia in dengue disease by enhancing platelet phagocytosis by macrophages.
authors.forename: Shu-Wen
authors.initials: SW
authors.lastname: Wan
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Yang
authors.forename: Ya-Ting
authors.initials: YT
authors.lastname: Chu
authors.forename: Chiou-Feng
authors.initials: CF
authors.lastname: Lin
authors.forename: Chih-Peng
authors.initials: CP
authors.lastname: Chang
authors.forename: Trai-Ming
authors.initials: TM
authors.lastname: Yeh
authors.forename: Robert
authors.initials: R
authors.lastname: Anderson
authors.affiliation: Prof. Yee-Shin Lin, Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, 1 University Road, Tainan 701, Taiwan, Tel.: +886 6 2353535 ext. 5646, Fax: +886 6 2082705, E-mail: yslin1@mail.ncku.edu.tw.
authors.forename: Yee-Shin
authors.initials: YS
authors.lastname: Lin
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D001792:Blood Platelets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002448:Cell Adhesion; D003715:Dengue / Q000276:immunology; D003716:Dengue Virus / Q000276:immunology*; D042783:Endothelial Cells / Q000166:cytology; D006801:Humans; D039661:Integrin beta3 / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008809:Mice, Inbred C3H; D010587:Phagocytosis; D010973:Platelet Adhesiveness; D011485:Protein Binding; D017452:Receptors, IgG / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013921:Thrombocytopenia / Q000276:immunology / Q000821:virology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; C061248:ITGB3 protein, human; D039661:Integrin beta3; C082515:NS1 protein, dengue-1 virus; D017452:Receptors, IgG; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D017361:Viral Nonstructural Proteins; D018799:Intercellular Adhesion Molecule-1
keywords: Dengue virus; nonstructural protein 1; platelet phagocytosis