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

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

来源：Thrombosis and Haemostasis, 2016, 115(3): 646-656.

DOI：10.1160/TH15-06-0498

• Dengue virus
• nonstructural protein 1
• platelet phagocytosis

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-alpha-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-alpha-activated ECs requires binding of Fc gamma R 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 beta 3 integrin expressed on ECs as well as the Fc gamma R 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.

• 出版日期2016-3