title: Reversal of West Nile virus-induced blood-brain barrier disruption and tight junction proteins degradation by matrix metalloproteinases inhibitor.
abstract: Though compromised blood-brain barrier (BBB) is a pathological hallmark of WNV-associated neurological sequelae, underlying mechanisms are unclear. We characterized the expression of matrix metalloproteinases (MMP) in WNV-infected human brain microvascular endothelial cells (HBMVE) and human brain cortical astrocytes (HBCA), components of BBB and their role in BBB disruption. Expression of multiple MMPs was significantly induced in WNV-infected HBCA cells. Naïve HBMVE cells incubated with the supernatant from WNV-infected HBCA cells demonstrated loss of tight junction proteins, which were rescued in the presence of MMP inhibitor, GM6001. Further, supernatant from WNV-infected HBCA cells compromised the in vitro BBB model integrity. Our data suggest astrocytes as one of the sources of MMP in the brain, which mediates BBB disruption allowing unrestricted entry of immune cells into the brain, thereby contributing to WNV neuropathogenesis. Because of the unavailability of WNV antivirals and vaccines, use of MMP inhibitors as an adjunct therapy to ameliorate WNV disease progression is warranted.
authors.affiliation: Retrovirology Research Laboratory, Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, Honolulu, HI 96813, USA.
authors.forename: Saguna
authors.initials: S
authors.lastname: Verma
authors.forename: Mukesh
authors.initials: M
authors.lastname: Kumar
authors.forename: Ulziijargal
authors.initials: U
authors.lastname: Gurjav
authors.forename: Stephanie
authors.initials: S
authors.lastname: Lum
authors.forename: Vivek R
authors.initials: VR
authors.lastname: Nerurkar
mesh_terms: D001253:Astrocytes / Q000378:metabolism / Q000821:virology; D001812:Blood-Brain Barrier / Q000473:pathology*; D062445:Claudin-1; D004151:Dipeptides / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism / Q000821:virology; D020869:Gene Expression Profiling; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000096:biosynthesis*; D008565:Membrane Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D019108:Tight Junctions / Q000473:pathology*; D014902:West Nile virus / Q000472:pathogenicity*; D062826:Zonula Occludens-1 Protein
chemical_list: C568108:CLDN1 protein, human; D062445:Claudin-1; D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; D008565:Membrane Proteins; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D010750:Phosphoproteins; D011480:Protease Inhibitors; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D020782:Matrix Metalloproteinases