title: West Nile virus-induced cell adhesion molecules on human brain microvascular endothelial cells regulate leukocyte adhesion and modulate permeability of the in vitro blood-brain barrier model.
abstract: Characterizing the mechanisms by which West Nile virus (WNV) causes blood-brain barrier (BBB) disruption, leukocyte infiltration into the brain and neuroinflammation is important to understand the pathogenesis of WNV encephalitis. Here, we examined the role of endothelial cell adhesion molecules (CAMs) in mediating the adhesion and transendothelial migration of leukocytes across human brain microvascular endothelial cells (HBMVE). Infection with WNV (NY99 strain) significantly induced ICAM-1, VCAM-1, and E-selectin in human endothelial cells and infected mice brain, although the levels of their ligands on leukocytes (VLA-4, LFA-1and MAC-1) did not alter. The permeability of the in vitro BBB model increased dramatically following the transmigration of monocytes and lymphocytes across the models infected with WNV, which was reversed in the presence of a cocktail of blocking antibodies against ICAM-1, VCAM-1, and E-selectin. Further, WNV infection of HBMVE significantly increased leukocyte adhesion to the HBMVE monolayer and transmigration across the infected BBB model. The blockade of these CAMs reduced the adhesion and transmigration of leukocytes across the infected BBB model. Further, comparison of infection with highly neuroinvasive NY99 and non-lethal (Eg101) strain of WNV demonstrated similar level of virus replication and fold-increase of CAMs in HBMVE cells suggesting that the non-neuropathogenic response of Eg101 is not because of its inability to infect HBMVE cells. Collectively, these results suggest that increased expression of specific CAMs is a pathological event associated with WNV infection and may contribute to leukocyte infiltration and BBB disruption in vivo. Our data further implicate that strategies to block CAMs to reduce BBB disruption may limit neuroinflammation and virus-CNS entry via 'Trojan horse' route, and improve WNV disease outcome.
authors.affiliation: Department of Tropical Medicine, Medical Microbiology and Pharmacology, Pacific Center for Emerging Infectious Diseases Research, John A Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
authors.forename: Kelsey
authors.initials: K
authors.lastname: Roe
authors.affiliation: Department of Tropical Medicine, Medical Microbiology and Pharmacology, Pacific Center for Emerging Infectious Diseases Research, John A Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
authors.forename: Beverly
authors.initials: B
authors.lastname: Orillo
authors.affiliation: Department of Tropical Medicine, Medical Microbiology and Pharmacology, Pacific Center for Emerging Infectious Diseases Research, John A Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, United States of America.
authors.forename: Saguna
authors.initials: S
authors.lastname: Verma
mesh_terms: D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000821:virology; D001921:Brain / Q000378:metabolism* / Q000821:virology; D002448:Cell Adhesion / Q000502:physiology*; D002478:Cells, Cultured; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology / Q000821:virology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D006801:Humans; D066298:In Vitro Techniques; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D009000:Monocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology; D010539:Permeability; D057705:Transendothelial and Transepithelial Migration / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*; D014901:West Nile Fever / Q000378:metabolism / Q000473:pathology / Q000821:virology; D014902:West Nile virus / Q000502:physiology*
chemical_list: D019040:E-Selectin; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1