Abstract
Typically occurring during secondary dengue virus (DENV) infections, dengue hemorrhagic fever (DHF) causes abnormal immune responses, as well as endothelial vascular dysfunction, for which the responsible viral factor remains unclear. During peak viremia, the plasma levels of virion-associated envelope protein domain III (EIII) increases to a point at which cell death is sufficiently induced in megakaryocytes in vitro. Thus, EIII may constitute a virulence factor for endothelial damage. In this study, we examined endothelial cell death induced by treatment with DENV and EIII in vitro. Notably, pyroptosis, the major type of endothelial cell death observed, was attenuated through treatment with Nlrp3 inflammasome inhibitors. EIII injection effectively induced endothelial abnormalities, and sequential injection of EIII and DENV-NS1 autoantibodies induced further vascular damage, liver dysfunction, thrombocytopenia, and hemorrhage, which are typical manifestations in DHF. Under the same treatments, pathophysiological changes in the Nlrp3 inflammasome–deficient mice were notably reduced compared with those in the wild-type mice. These results suggest that the Nlrp3 inflammasome constitutes a potential therapeutic target for treating DENV-induced hemorrhage in DHF.
Highlights
Dengue virus (DENV) infection is one of the most rapidly growing mosquito‐borne infections [1, 2]
In analyses of proinflammatory and proapoptotic responses and soluble thrombomodulin release, which is a marker of endothelial damage [28], we observed that treatment with levels of rEIII and DENV equivalent to the dengue hemorrhagic fever (DHF) viral load induced death of HMEC-1 cells
Results from annexin V staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), propidine iodide (PI) staining, and caspase assays suggested the involvement of apoptosis in DENV-induced endothelial cell death [29, 30]
Summary
Dengue virus (DENV) infection is one of the most rapidly growing mosquito‐borne infections [1, 2]. Secondary DENV infections are epidemiologically associated with an increased risk of life-threatening severe dengue [classically known as dengue hemorrhagic fever (DHF)]. No specific antiviral treatments against DENV infection have been developed. Overall mortality rates from infectious diseases decreased from 2005 to 2015, mortality attributable to DENV infection increased by 48.7% [3]. Endothelial damage and vascular leakage are the hallmarks of severe dengue. Vascular leakage, which occurs during the acute phase of DHF, typically manifests 3–6 days after disease onset [4, 5]. The fact that DHF acute phase follows
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