Essential role of RIG-I in the activation of endothelial cells by dengue virus

Abstract

Dengue virus (DENV) infection is associated to exacerbated inflammatory response and structural and functional alterations in the vascular endothelium. However, the mechanisms underlying DENV-induced endothelial cell activation and their role in the inflammatory response were not investigated so far. We demonstrated that human brain microvascular endothelial cells (HBMECs) are susceptible to DENV infection, which induces the expression of the cytoplasmic pattern recognition receptor (PRR) RIG-I. Infection of HBMECs promoted an increase in the production of type I IFN and proinflammatory cytokines, which were abolished after RIG-I silencing. DENV-infected HBMECs also presented a higher ICAM-1 expression dependent on RIG-I activation as well. On the other hand, ablation of RIG-I did not interfere with virus replication. Our data suggest that RIG-I activation by DENV may participate in the disease pathogenesis through the modulation of cytokine release and expression of adhesion molecules, probably contributing to leukocyte recruitment and amplification of the inflammatory response.

Dengue Virus neither Directly Mediates Hyperpermeability nor Enhances Tumor Necrosis Factor-^|^alpha;-Induced Permeability In Vitro

“…Although we have reason to believe that recruitment of effector cells may play a role in this phenomenon, DENV infection directly activated ECs by up-regulation of the intercellular adhesion molecule in a dose-dependent manner (data not shown), in accordance with that reported elsewhere (47). It is well known that activated ECs facilitate leukocyte adherence and, in turn, activate cell adherence (48).…”

Interplay between Inflammation and Cellular Stress Triggered by Flaviviridae Viruses

“…Monocytes, macrophages and non-immune cells, such as endothelial cells, epithelial cells and hepatocytes usually sense RNA virus through RIG-I and/or TLR3; whereas TLR7 is highly expressed and is the major RNA sensor in plasmacytoid dendritic cells (pDC; Sun P. et al, 2009; Tsai et al, 2009; Nasirudeen et al, 2011; Qin et al, 2011; da Conceição et al, 2013). Activation of either RLRs or TLRs may promote the secretion of interferons and proinflammatory cytokines.…”

“…Both RIG-I and MDA5 were shown to be up regulated and involved in IFN-β induction upon DENV and WNV infection in hepatocytes and endothelial cells (Loo et al, 2008; Nasirudeen et al, 2011; da Conceição et al, 2013). RIG-I, MDA5 and MAVS were, then, associated to increased secretion of inflammatory mediators, which have been also observed in patients’ plasma.…”

Soluble mediators produced by the crosstalk between microvascular endothelial cells and dengue-infected primary dermal fibroblasts inhibit dengue virus replication and increase leukocyte transmigration

“…For example, studies with mouse cytomegalovirus demonstrated that activation and maturation of DCs are dependent on the activation of NK cells [12][13][14]. In vitro evidence of immune cellular communication during flavivirus infection has also been reported [3,15].…”

“…NK cells imparts both immunomodulatory and antiviral effects on primary monocyte-derived DCs infected with Japanese encephalitis virus as well [15]. It has been suggested that the response of skin-resident cells to DENV can influence the outcome of infection [4,10].…”