The role of vascular leak in hemorrhagic fever virus pathogenesis
Description
Hemorrhagic fever viruses cause diseases ranging from nonspecific febrile illnesses to severe vascular permeability, edema, coagulation defects, and shock. However, the mechanism that these viruses use to cause this spectrum of diseases is not well characterized. Endothelial cells are a key structural component of blood vessels and they also act as a barrier between blood and tissues. These cells serve an immunologic function by recognizing pathogens, expressing soluble mediators, and interacting with other immune system cells for their extravasation across the endothelium. The aim of this study was to isolate specific virus/endothelial cells interactions to determine factors that lead to an increase in endothelium permeability. It was determined that microvascular endothelial cells infected with Dengue virus, a member of the Flaviviridae family, induced an increase in permeability that was attributed to expression of the cytokine TNF-alpha and subsequent apoptosis of the cell. With the addition of neutralizing TNF-alpha antibodies or a general caspase inhibitor, Dengue virus-induced permeability was reduced as well as the number of apoptotic cells. Endothelial cells infected with Pichinde virus, a member of the Arenaviridae family, also exhibited an increase in permeability. Through the use of gene expression arrays and inhibitors to specific physiological functions and pathways, it was determined that the production of nitric oxide led to Pichinde virus-induced permeability. This permeability could be abrogated with the incorporation of a nitric oxide synthase inhibitor. This series of in vitro experiments has demonstrated that hemorrhagic fever viruses utilize a variety of different methods in order to cause vascular permeability in human endothelial cells. This study also provides the basework for future in vivo experiments utilizing small animal models of viral hemorrhagic fevers (VHF)