Abstract
Dengue virus (DENV) infection causes a characteristic pathology in humans involving dysregulation of the vascular system. In some patients with dengue hemorrhagic fever (DHF), vascular pathology can become severe, resulting in extensive microvascular permeability and plasma leakage into tissues and organs. Mast cells (MCs), which line blood vessels and regulate vascular function, are able to detect DENV in vivo and promote vascular leakage. Here, we identified that a MC-derived protease, tryptase, is consequential for promoting vascular permeability during DENV infection, through inducing breakdown of endothelial cell tight junctions. Injected tryptase alone was sufficient to induce plasma loss from the circulation and hypovolemic shock in animals. A potent tryptase inhibitor, nafamostat mesylate, blocked DENV-induced vascular leakage in vivo. Importantly, in two independent human dengue cohorts, tryptase levels correlated with the grade of DHF severity. This study defines an immune mechanism by which DENV can induce vascular pathology and shock.
Highlights
Dengue virus (DENV) causes an acute viral infection that manifests as a broad spectrum of disease: from asymptomatic infection to a mild febrile illness, dengue fever (DF), which may resolve within 2 weeks to the most severe form, dengue hemorrhagic fever (DHF), which involves vascular leakage as the primary potentially life-threatening sign
Our previous studies showed that the transendothelial resistance (TER) was dramatically reduced when endothelial monolayers were treated with dengue virus (DENV)-elicited Mast cells (MCs) products compared with the control untreated groups, groups treated with supernatants from mock-infected MCs, or groups treated with an equivalent amount of DENV in media alone [34]
In the absence of strong and consistent evidence that endothelial cells are directly infected by DENV in humans, immunemediated pathology is presumed to underlie the mechanism of increased endothelial permeability during DHF and dengue shock syndrome (DSS) [2]
Summary
Dengue virus (DENV) causes an acute viral infection that manifests as a broad spectrum of disease: from asymptomatic infection to a mild febrile illness, dengue fever (DF), which may resolve within 2 weeks to the most severe form, dengue hemorrhagic fever (DHF), which involves vascular leakage as the primary potentially life-threatening sign. The predominant view of the field is that vascular leakage in humans results from immune-mediated pathology rather than infection of endothelial cells themselves [2]. One theory is that “cytokine storm” damages the vascular endothelium during infection. These cytokines could be derived from infected cells that contain replicating virus or other immune cells
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