Bluetongue Virus and Double-Stranded RNA Increase Human Vascular Permeability: Role of p38 MAPK

Abstract

Endothelial cell (EC) involvement in viral hemorrhagic fevers has been clearly established. However, virally activated mechanisms leading to endothelial activation and dysfunction are not well understood. Several different potential mechanisms such as direct viral infection, alterations in procoagulant/anticoagulant balance, and increased cytokine production have been suggested. We utilized a model of EC barrier dysfunction and vascular endothelial leakage to explore the effect of bluetongue virus (BTV), a hemorrhagic fever virus of ruminants, on human lung endothelial cell barrier properties. Infection of human lung EC with BTV induced a significant and dose-dependent decrease in trans-endothelial electrical resistance (TER). Furthermore, decreases in TER occurred in conjunction with cytoskeletal rearrangement, suggesting a direct mechanism for viral infection-mediated endothelial barrier disruption. Interestingly, double-stranded RNA (dsRNA) mimicked the effects of BTV on endothelial barrier properties. Both BTV- and dsRNA-induced endothelial barrier dysfunction was blocked by treatment with a pharmacological inhibitor of p38 MAPK. The induction of vascular permeability by dsRNA treatment or BTV infection was concomitent with induction of inflammatory cytokines. Taken together, our data suggest that the presence of dsRNA during viral infections and subsequent activation of p38 MAPK is a potential molecular pathway for viral induction of hemorrhagic fevers. Collectively, our data suggest that inhibition of p38 MAPK may be a possible therapeutic approach to alter viral-induced acute hemorrhagic diseases.

MAPK and heat shock protein 27 activation are associated with respiratory syncytial virus induction of human bronchial epithelial monolayer disruption

“…We (8) have recently reported that infection of endothelial cells with BTV, a hemorrhagic virus, resulted in the induction of membrane permeability through the activation of p38 MAPK pathway.…”

“…Lung epithelial membrane permeability was measured by using an electrical cell-substrate impedance sensing system (ECIS; Applied BioPhysics, Troy, NY) as previously described (4,8). PHBE or A549 cells were plated onto gold-evaporated electrodes (8W10E, Applied BioPhysics) at a density of 150,000 cells per well and grown to a confluent monolayer.…”

“…RSV can also induce other severe respiratory infections such as acute respiratory distress syndrome and acute lung injury, both of which involve endothelial and epithelial membrane dysfunction (8,19,46). RSV infection starts in the upper airway epithelial cells, but it can spread to the lower airways and cause severe bronchiolitis, which is manifested by inflammatory cell infiltration, mucus secretion, and edema (12,18,36,41).…”

“…We (8) previously reported that infection of human endothelial cells with bluetongue virus (BTV), a hemorrhagic fever virus of the ruminants, caused transendothelial barrier disruption. The BTV-induced endothelial barrier dysfunction was mediated by the activation of p38 MAPK pathway, which has been established as a critical signaling pathway for vascular endothelial permeability induced by different stimuli (2,3).…”

Bluetongue virus: virology, pathogenesis and immunity

“…BTV reduces endothelial electrical resistance in vitro associated to p38 MAP kinase-dependent cytoskeletal rearrangements [14]. In addition, BTV infections induce cell death in many cell types and an important inflammatory cell response.…”