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 activity in vivo and in vitro. Infected 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-1 in vivo) infected ex vivo with 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 infected in vivo by 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.IMPORTANCE RNA 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 vivo MAV-1 infection of these cell types caused higher MMP activity than mock infection, suggesting that they may contribute to the higher MMP activity seen in vivo. To our knowledge, this provides the first evidence of an encephalitic DNA virus in its natural host causing increased MMP activity in brains.

MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

“…Mouse adenovirus type-1 (MAV-1) infection increases levels of MMP-2 and -9 in brains [162]. Additional ex vivo data revealed that MMP-2 and -9 are produced by astrocytes and microglia in response to mouse encephalitic adenovirus-1, which might contribute to BBB disruption and encephalitis [163]. MAV-1 may also induce BBB breakdown by reducing surface expression of TJ proteins occludin and claudin-5 [164].…”

Age-Dependent Effects of Immunoproteasome Deficiency on Mouse Adenovirus Type 1 Pathogenesis

“…However, the results of our rechallenge experiments suggested that immunoproteasome deficiency was not likely to have substantially altered production of neutralizing antibodies to MAV-1. To verify this, we assessed the ability of serum obtained from B6 and TKO mice at 21 dpi to neutralize in vitro infection of 3T12 mouse fibroblasts by MAV-1.pIXeGFP, a recombinant green fluorescent protein (GFP)-expressing MAV-1 (14,15). Preincubation of virus with serum from infected B6 or TKO mice inhibited viral replication, assayed by measuring fluorescence in wells of infected cells (Fig.…”

Murine adenoviruses: tools for studying adenovirus pathogenesis in a natural host

“…In contrast to HAdVs, which have an epithelial tropism, MAdV‐1 primarily infects endothelial cells and monocytes/macrophages, and astrocytes can also be infected . The virus causes a pantropic infection; high levels of virus found in the central nervous system (CNS) lead to increased permeability of the blood–brain barrier, accompanied by altered tight junction‐protein expression and encephalitis .…”

“…The virus causes a pantropic infection; high levels of virus found in the central nervous system (CNS) lead to increased permeability of the blood–brain barrier, accompanied by altered tight junction‐protein expression and encephalitis . MAdV‐1 CNS infection is characterized by viral brain loads that correlate with disease severity and induction of matrix metalloproteinase (MMP) activity . Enzyme activity of MMP2 and MMP9, which are induced in brains during microbial infection or neurological disease, is increased in mice and cultured cells upon MAdV‐1 infection.…”

“…Mouse adenovirus MAdV‐1 (Ad‐FL) was among the first nonprimate adenoviruses identified in the 1950s and 1960s, along with canine hepatitis virus, CAdV‐1 , fowl AdV‐1 (CELO), and bovine AdV . MAdV‐1 has a tropism for endothelial cells and cells of the monocyte/macrophage lineage, and it also infects astrocytes . MAdV‐1 infects tissues throughout the mouse, and the highest levels of virus are found in the brain, spinal cord, and spleen after intraperitoneal infection .…”