Anti-dengue virus nonstructural protein 1 antibodies contribute to platelet phagocytosis by macrophages

Shu-Wen Wan; Yi-Wen Yang; Ya-Ting Chu; Chiou-Feng Lin; Chih-Peng Chang; Trai-Ming Yeh; Robert Anderson; Yee-Shin Lin

doi:10.1160/th15-06-0498

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 115(03): 646-656
DOI: 10.1160/th15-06-0498

Blood Cells, Inflammation and Infection

Schattauer GmbH

Anti-dengue virus nonstructural protein 1 antibodies contribute to platelet phagocytosis by macrophages

Shu-Wen Wan^†

¹Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan

²Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

,

Yi-Wen Yang^†

²Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

,

Ya-Ting Chu

²Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

,

Chiou-Feng Lin

¹Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan

³Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, Taipei, Taiwan

,

Chih-Peng Chang

¹Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan

²Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

,

Trai-Ming Yeh

¹Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan

⁴Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

,

Robert Anderson

^5;Departments of Microbiology & Immunology and Pediatrics, and Canadian Center for Vaccinology, Dalhousie University, Halifax, Nova Scotia, Canada

,

Yee-Shin Lin

¹Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan

²Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

› Author Affiliations

Abstract

Summary

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.

Keywords

Dengue virus - nonstructural protein 1 - platelet phagocytosis

Full Text

References

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