Abstract
In tropical and subtropical regions, mosquito-borne dengue virus (DENV) infections can lead to severe dengue, also known as dengue hemorrhage fever, which causes bleeding, thrombocytopenia, and blood plasma leakage and increases mortality. Although DENV-induced platelet cell death was linked to disease severity, the role of responsible viral factors and the elicitation mechanism of abnormal platelet activation and cell death remain unclear. DENV and virion-surface envelope protein domain III (EIII), a cellular binding moiety of the virus particle, highly increase during the viremia stage. Our previous report suggested that exposure to such viremia EIII levels can lead to cell death of endothelial cells, neutrophils, and megakaryocytes. Here we found that both DENV and EIII could induce abnormal platelet activation and predominantly necrotic cell death pyroptosis. Blockages of EIII-induced platelet signaling using the competitive inhibitor chondroitin sulfate B or selective Nlrp3 inflammasome inhibitors OLT1177 and Z-WHED-FMK markedly ameliorated DENV- and EIII-induced thrombocytopenia, platelet activation, and cell death. These results suggest that EIII could be considered as a virulence factor of DENV, and that Nlrp3 inflammasome is a feasible target for developing therapeutic approaches against dengue-induced platelet defects.
Highlights
Dengue, caused by dengue virus (DENV), is a commonly observed mosquito-borne infectious disease in the tropical and subtropical areas of the world [1, 2]
Mouse experiments further revealed that similar to challenges with DENV, injections of recombinant EIII (rEIII) but not those of rGST induced thrombocytopenia and shortened plasma clotting time in vivo (Figure 2). These results suggest that exposure of DENV and virion-surface envelope protein domain III (EIII) to platelets and plasma is sufficient, leading to an abnormal coagulation response
Because annexin V and caspase signals can be detected in both apoptotic and nonapoptotic cell death [45,46,47,48,49], we investigated whether nonapoptotic, regulated cell death (RCD) pathways are involved in DENV- and rEIII-induced platelet death
Summary
Dengue, caused by dengue virus (DENV), is a commonly observed mosquito-borne infectious disease in the tropical and subtropical areas of the world [1, 2]. Over half of the global population lives in areas with DENV infection risk, resulting in 96 million patients with symptomatic dengue every year [9]. The primary infection of DENV is a self-limiting dengue fever (DF), whereas secondary infections are epidemiologically associated with an increased risk of life-threatening severe dengue [ known as dengue hemorrhage fever (DHF)]. Dengue EIII Induces Platelet Pyroptosis defects are the frequently observed symptoms in both primary and secondary dengue infection; the responsible pathogenic factor remains unclear. We hypothesize that the DENV envelope protein (E) domain III (EIII) can be one of the viral factors responsible for pathological changes in platelets
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