Extracellular vesicles from CLEC2-activated platelets enhance dengue virus-induced lethality via CLEC5A/TLR2
Journal
Nature Communications
Journal Volume
10
Journal Issue
1
Pages
2402
Date Issued
2019
Author(s)
Abstract
Platelet-leukocyte interactions amplify inflammatory reactions, but the underlying mechanism is still unclear. CLEC5A and CLEC2 are spleen tyrosine kinase (Syk)-coupled C-type lectin receptors, abundantly expressed by leukocytes and platelets, respectively. Whereas CLEC5A is a pattern recognition receptor (PRR) to flaviviruses and bacteria, CLEC2 is the receptor for platelet-activating snake venom aggretin. Here we show that dengue virus (DV) activates platelets via CLEC2 to release extracellular vesicles (EVs), including exosomes (EXOs) and microvesicles (MVs). DV-induced EXOs (DV-EXOs) and MVs (DV-MVs) further activate CLEC5A and TLR2 on neutrophils and macrophages, thereby induce neutrophil extracellular trap (NET) formation and proinflammatory cytokine release. Compared to stat1?/? mice, simultaneous blockade of CLEC5A and TLR2 effectively attenuates DV-induced inflammatory response and increases survival rate from 30 to 90%. The identification of critical roles of CLEC2 and CLEC5A/TLR2 in platelet-leukocyte interactions will support the development of novel strategies to treat acute viral infection in the future. ? 2019, The Author(s).
SDGs
Other Subjects
c type lectin domain containing 5a; c type lectin like receptor 2; CD63 antigen; CD81 antigen; CD9 antigen; lectin; PADGEM protein; pattern recognition receptor; snake venom; toll like receptor 2; unclassified drug; cell surface receptor; CLEC1B protein, human; CLEC5A protein, human; Clec5a protein, mouse; cytokine; lectin; STAT1 protein; Stat1 protein, mouse; Tlr2 protein, mouse; toll like receptor 2; cell; chemical reaction; dengue fever; induced response; virus; animal cell; animal experiment; animal model; animal tissue; Article; blood vessel permeability; cell membrane permeability; cell stimulation; confocal microscopy; controlled study; cytokine release; dengue; Dengue virus; enzyme linked immunosorbent assay; exosome; extracellular trap; female; flow cytometry; human; human cell; immunofluorescence; immunohistochemistry; inflammation; lethality; macrophage; male; mass spectrometry; membrane microparticle; mouse; neutrophil; nonhuman; pathogenesis; real time polymerase chain reaction; RNA isolation; survival rate; thrombocyte activation; transmission electron microscopy; upregulation; virus infection; Western blotting; animal; Dengue virus; exosome; genetics; immunology; knockout mouse; metabolism; thrombocyte; thrombocyte activation; virology; Dengue virus; Mus; Animals; Blood Platelets; Cell-Derived Microparticles; Cytokines; Dengue; Dengue Virus; Exosomes; Extracellular Traps; Extracellular Vesicles; Humans; Inflammation; Lectins, C-Type; Macrophages; Mice; Mice, Knockout; Neutrophils; Platelet Activation; Receptors, Cell Surface; STAT1 Transcription Factor; Survival Rate; Toll-Like Receptor 2
Type
journal article