The BBB is a selective cellular border made up of specialized cerebral microvascular endothelial cells that protects the CNS from blood-borne dangers. The BBB-endothelial cells interacts with perivascular structures like pericytes and astrocytes and have characteristic properties GDC-0879 905281-76-7 defined by high transendothelial electrical resistance, the expression of tight junction proteins sealing the paracellular spaces, and a low pinocytotic activity. These features limit transcellular and paracellular movement of peripheral immune cells and molecules. However, infection with neurotropic pathogens results in increased migration of leukocytes into the CNS, a key element of innate and adaptive immunity. Leukocyte trafficking across the BBB, a very coordinated process including tethering, rolling and adhesion followed by transmigration, is governed by the interactions of endothelial cell adhesion molecules with their ligands, matrix metalloproteinases and chemokines. Endothelial CAMs such as immunoglobulin superfamily members and selectins interact with their leukocyte integrins counterparts and, in concert with chemotactic chemokines, facilitate rolling and adhesion of leukocytes on the endothelial wall. Under healthy conditions the endothelial cells of the BBB express very low levels of CAMs, however the expression of multiple CAMs including ICAM-1, VCAM-1, and selectins upon inflammatory stimulation multiple sclerosis or infection with viruses such as human immunodeficiency virus and herpes simplex virus. Our recent study demonstrated that the disruption of BBB in WNV-infected mice correlated with loss of TJPs and increased MMPs in the brain. Using a human in vitro BBB model we have also shown that the transit of cell-free virus does not alter the permeability of the model. In addition, we observed that WNV-induced expression of MMP-9 and -3 in human primary astrocytes, but not human brain microvascular endothelial cells, is responsible for the degradation of TJP of HBMVE cells, suggesting that WNV-induced neuroinflammation may contribute to BBB disruption. Infiltrating macrophages and T cells are critical for controlling infection and clearing WNV in the brain. Conversely, they are also proposed to be a route of virus-CNS entry and source of high levels of proinflammatory cytokines and chemokines in the brain. However, little is known about the underlying mechanisms of leukocyte transmigration and their role in BBB disruption associated with WNV infection. Therefore, the objective of the present study was to use transwell cultures of brain endothelial cells to examine the effect of leukocyte transmigration on the permeability of the in vitro BBB model and to further understand the role of WNV-induced CAMs in the transmigration of leukocytes across the BBB. Our results report CAMs such as ICAM-1, VCAM-1, and E-selectin are induced following WNV infection in human endothelial cells and mouse brain, blocking of which results in significant reduction of the adhesion of leukocytes to HBMVE cells and disruption of BBB model.