title: Matrix Metalloproteinase Activity in Infections by an Encephalitic Virus, Mouse Adenovirus Type 1.
abstract: Mouse adenovirus type 1 (MAV-1) infection causes encephalitis in susceptible strains of mice and alters the permeability of infected brains to small molecules, which indicates disruption of the blood-brain barrier (BBB). Under pathological conditions, matrix metalloproteinases (MMPs) can disrupt the BBB through their proteolytic activity on basement membrane and tight junction proteins. We examined whether MAV-1 infection alters MMP activityin vivoandin vitroInfected MAV-1-susceptible SJL mice had higher MMP2 and MMP9 activity in brains, measured by gelatin zymography, than mock-infected mice. Infected MAV-1-resistant BALB/c mice had MMP activity levels equivalent to those in mock infection. Primary SJL mouse brain endothelial cells (a target of MAV-1in vivo) infectedex vivowith MAV-1 had no difference in activities of secreted MMP2 and MMP9 from mock cells. We show for the first time that astrocytes and microglia are also infectedin vivoby MAV-1. Infected mixed primary cultures of astrocytes and microglia had higher levels of MMP2 and MMP9 activity than mock-infected cells. These results indicate that increased MMP activity in the brains of MAV-1-infected susceptible mice may be due to MMP activity produced by endothelial cells, astrocytes, and microglia, which in turn may contribute to BBB disruption and encephalitis in susceptible mice.IMPORTANCERNA and DNA viruses can cause encephalitis; in some cases, this is accompanied by MMP-mediated disruption of the BBB. Activated MMPs degrade extracellular matrix and cleave tight-junction proteins and cytokines, modulating their functions. MAV-1 infection of susceptible mice is a tractable small-animal model for encephalitis, and the virus causes disruption of the BBB. We showed that MAV-1 infection increases enzymatic activity of two key MMPs known to be secreted and activated in neuroinflammation, MMP2 and MMP9, in brains of susceptible mice. MAV-1 infects endothelial cells, astrocytes, and microglia, cell types in the neurovascular unit that can secrete MMPs.Ex vivoMAV-1 infection of these cell types caused higher MMP activity than mock infection, suggesting that they may contribute to the higher MMP activity seenin vivoTo our knowledge, this provides the first evidence of an encephalitic DNA virus in its natural host causing increased MMP activity in brains.
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Shanna L
authors.initials: SL
authors.lastname: Ashley
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Carla D
authors.initials: CD
authors.lastname: Pretto
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Stier
authors.affiliation: Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Padma
authors.initials: P
authors.lastname: Kadiyala
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Luiza
authors.initials: L
authors.lastname: Castro-Jorge
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Tien-Huei
authors.initials: TH
authors.lastname: Hsu
authors.affiliation: Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Doherty
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Carnahan
authors.affiliation: Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Castro
authors.affiliation: Departments of Neurosurgery and Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Pedro R
authors.initials: PR
authors.lastname: Lowenstein
authors.affiliation: Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA krspin@umich.edu.
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Spindler
mesh_terms: D000257:Adenoviridae Infections / Q000473:pathology* / Q000821:virology; D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000821:virology; D001921:Brain / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018792:Encephalitis, Viral / Q000473:pathology* / Q000821:virology; D042783:Endothelial Cells / Q000201:enzymology / Q000821:virology; D017921:Mastadenovirus / Q000472:pathogenicity*; D020778:Matrix Metalloproteinase 2 / Q000032:analysis*; D020780:Matrix Metalloproteinase 9 / Q000032:analysis*; D051379:Mice; D017628:Microglia / Q000201:enzymology / Q000821:virology
chemical_list: D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: astrocytes; encephalitis; endothelial; endothelial cells; matrix metalloproteinase; microglia