Abstract
Exacerbated inflammatory response and altered vascular function are hallmarks of dengue disease. Reactive oxygen species (ROS) production has been associated to endothelial barrier disturbance and microvascular alteration in distinct pathological conditions. Increased ROS has been reported in in vitro models of dengue virus (DENV) infection, but its impact for endothelial cell physiology had not been fully investigated. Our group had previously demonstrated that infection of human brain microvascular endothelial cells (HBMEC) with DENV results in the activation of RNA sensors and production of proinflammatory cytokines, which culminate in cell death and endothelial permeability. Here, we evaluated the role of mitochondrial function and NADPH oxidase (NOX) activation for ROS generation in HBMEC infected by DENV and investigated whether altered cellular physiology could be a consequence of virus-induced oxidative stress. DENV-infected HBMECs showed a decrease in the maximal respiratory capacity and altered membrane potential, indicating functional mitochondrial alteration, what might be related to mtROS production. Indeed, mtROS was detected at later time points after infection. Specific inhibition of mtROS diminished virus replication, cell death, and endothelial permeability, but did not affect cytokine production. On the other hand, inhibition of NOX-associated ROS production decreased virus replication and cell death, as well as the secretion of inflammatory cytokines, including IL-6, IL-8, and CCL5. These results demonstrated that DENV replication in endothelial cells induces ROS production by different pathways, which impacts biological functions that might be relevant for dengue pathogenesis. Those data also indicate oxidative stress events as relevant therapeutical targets to avoid vascular permeability, inflammation, and neuroinvasion during DENV infection.
Highlights
Dengue virus (DENV) infection is a major public health problem worldwide, mostly in tropical and subtropical countries, affecting about 400 million people every year [1]
We have previously demonstrated that human brain microvascular endothelial cells (HBMECs) are permissive to DENV, and virus replication triggers the activation of RNA sensors, inducing the production of inflammatory cytokines, chemokines and type I interferon [9]
Our group demonstrated that infection of HBMEC with DENV2 induced RIG-I expression, cytokine production, and cell death [9, 12]
Summary
Dengue virus (DENV) infection is a major public health problem worldwide, mostly in tropical and subtropical countries, affecting about 400 million people every year [1]. Vascular alterations, including vasodilation and increased permeability, are major consequences of DENV infection, contributing to plasma extravasation to the tissues, hemorrhagic manifestations, and hypotension, which are hallmarks of severe disease, but may happen at lower levels in mild and moderate disease [3, 4]. A number of studies have been unraveling the complex connections between virus sensing, cellular stress response and cell death [rev in [13]]. Some of those signals converge to the production of nitrogen and oxygen reactive species, which accumulation stimulate the secretion of inflammatory mediators, and trigger autophagy, apoptosis and necroptosis in different models of viral infections [14,15,16,17,18]. It has been largely demonstrated that excessive ROS impair microvessel integrity and that leukocyte-derived ROS might be an important contributor to endothelial barrier damage [rev in [21]], the role of endogenous endothelial cellderived ROS has been poorly addressed, especially in the context of virus infections
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