Dengue Virus Infection Differentially Regulates Endothelial Barrier Function over Time through Type I Interferon Effects

Dengue is caused by infection with one of the dengue viruses (DENVs), a group of 4 antigenically related mosquito-borne flaviviruses [1]. Dengue is the most prevalent arboviral disease worldwide and produces significant morbidity and mortality throughout the tropics and subtropics [2]. DENV infections produce a wide spectrum of clinical illness, ranging from asymptomatic or mild illness to a severe and life-threatening disease—dengue hemorrhagic fever (DHF). The hallmark of DHF is vascular endothelial dysfunction manifested by a vascular leakage syndrome and sometimes a hemorrhagic diathesis. The morbidity and mortality of DHF are largely driven by the vascular leakage and its ensuing complications. The mechanisms of endothelial barrier dysfunction that lead to the unique vascular leakage syndrome of DHF are poorly understood. The DENVs are not cytopathic to endothelial cells in vitro [3, 4]. Viral antigen–positive endothelial cells have been seen in autopsy tissues with minimal or no endothelial destruction [5, 6]. Plasma leakage develops abruptly during viral clearance and early symptom recovery, at a time of significant immune activation [7]. The initial plasma leakage is focal and occurs predominantly in the pleural and peritoneal spaces [8]. The prevailing explanation for vascular leakage in DHF is that immune responses to DENV infection produce a cytokine storm that leads to the transient compromise of endothelial barrier function [7]. Many proinflammatory cytokines, angiogenesis factors, and other mediators (e.g., thrombin, metalloproteinases, and prostaglandins) can decrease endothelial barrier function and thereby increase vascular permeability [9]. Circulating levels of many vascular permeability mediators are indeed elevated in patients with DHF [7, 10-12] and can be produced by DENV-infected cells in vitro [13, 14]. However, increased levels of these soluble mediators are also present in other diverse inflammatory conditions, such as bacterial sepsis [15], cerebral malaria [16], autoimmune diseases [17], and malignancies [18]. The vascular leakage characteristics of these varied conditions are distinct from those of DHF. We hypothesized that direct viral effects on the responsiveness of endothelium to inflammatory and angiogenesis mediators are responsible for the vascular leakage characteristics of DHF. We found that DENV type 2 (DENV2) infection could suppress tumor necrosis factor (TNF)–α–mediated hyperpermeability in human umbilical vein endothelial cell (HUVEC) monolayers. This suppressive effect was seen up to 72 h after DENV2 infection. However, 1 week after infection TNF-α–mediated hyperpermeability was enhanced in DENV2-infected endothelium, compared with that in uninfected endothelium. The present study elucidates the critical role played by DENV and TNF-α–induced type I interferon (IFN) in the modulation of endothelial barrier function over time. Our results provide the foundation for a rational model of vascular leakage in DHF and potential therapeutic approaches.