Reovirus infection of the CNS enhances iNOS expression in areas of virus-induced injury.
Nitric oxide (NO) has been implicated as a contributor to the host's innate defense against viral infections including those affecting the CNS. Reovirus infection of the CNS is a classic experimental system for understanding the pathogenesis of neurotropic viral infection. Infection with serotype 3 strains is associated with perturbations in various cellular signaling pathways including NF-kappaB and NO plays a regulatory role in many of these same pathways. We therefore examined whether NO production is dysregulated following reovirus serotype 3 strain Abney (T3A) infection of the mouse CNS. Nitric oxide synthase (NOS) activity was significantly higher in brain homogenates from T3A-infected animals compared to mock infected. Increased NOS activity correlated with inducible NOS (iNOS) expression in brain homogenates of T3A-infected animals. Expression of iNOS was confined to areas of viral infection and injury. T3A infection of primary neuronal and glial cultures was also associated with enhanced expression of iNOS. Immunocytochemical studies of primary glial cultures demonstrated that, in addition to its known neuronotropism, T3A was also capable of infecting immature microglial cells. T3A infection did not alter expression of either neuronal or endothelial NOS isoforms in neuronal or glial cultures or in mouse brain. The NO donor S-Nitroso-N-acetyl penicillamine (SNAP) significantly inhibited T3A growth in neuronal cultures, conversely the NOS inhibitor N-omega-Nitro-L-arginine methyl ester hydrochloride (L-NAME) augmented viral growth. Our findings provide the first evidence of reovirus-induced iNOS expression and the first demonstration that NO inhibits mammalian reovirus replication, suggesting that NO may play an antiviral role during reovirus infection.
Goody
Robin J
RJ
Department of Neurology, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA.
Hoyt
Cristen C
CC
Tyler
Kenneth L
KL
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology / Q000821:virology; D015153:Blotting, Western / Q000379:methods; D002452:Cell Count; D002478:Cells, Cultured; D002490:Central Nervous System / Q000033:anatomy & histology / Q000201:enzymology* / Q000821:virology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts; D005786:Gene Expression Regulation / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D012089:Mammalian orthoreovirus 3; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000201:enzymology / Q000821:virology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000821:virology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D012088:Reoviridae Infections / Q000378:metabolism*; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D013997:Time Factors
D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D006023:Glycoproteins; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; C473590:isolectin B4-binding glycoprotein, mouse; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester