ABSTRACT
We have recently demonstrated that increased blood-CNS barrier permeability and CNS inflammation in a conventional mouse model of experimental allergic encephalomyelitis are dependent upon the production of peroxynitrite (ONOO(-)), a product of the free radicals NO* and superoxide (O2*(-)). To determine whether this is a reflection of the physiological contribution of ONOO(-) to an immune response against a neurotropic pathogen, we have assessed the effects on adult rats acutely infected with Borna disease virus (BDV) of administration of uric acid (UA), an inhibitor of select chemical reactions associated with ONOO(-). The pathogenesis of acute Borna disease in immunocompetent adult rats results from the immune response to the neurotropic BDV, rather than the direct effects of BDV infection of neurons. An important stage in the BDV-specific neuroimmune response is the invasion of inflammatory cells into the CNS. UA treatment inhibited the onset of clinical disease, and prevented the elevated blood-brain barrier permeability as well as CNS inflammation seen in control-treated BDV-infected rats. The replication and spread of BDV in the CNS were unchanged by the administration of UA, and only minimal effects on the immune response to BDV Ags were observed. These results indicate that the CNS inflammatory response to neurotropic virus infection is likely to be dependent upon the activity of ONOO(-) or its products on the blood-brain barrier.
Subject(s)
Blood-Brain Barrier/drug effects , Borna Disease/immunology , Borna disease virus/immunology , Brain/immunology , Chemotaxis, Leukocyte/physiology , Encephalitis, Viral/immunology , Free Radical Scavengers/therapeutic use , Neuroprotective Agents/therapeutic use , Peroxynitrous Acid/physiology , Tyrosine/analogs & derivatives , Uric Acid/therapeutic use , Acute Disease , Animals , Antigens, Viral/immunology , Borna Disease/pathology , Borna Disease/virology , Borna disease virus/physiology , Brain/metabolism , Brain/pathology , Brain/virology , Brain Chemistry/drug effects , Chemotaxis, Leukocyte/drug effects , Encephalitis, Viral/pathology , Encephalitis, Viral/virology , Female , Free Radical Scavengers/pharmacology , Free Radicals , Gene Expression Profiling , Immunocompetence , Inflammation , Lymphocyte Count , Nerve Tissue Proteins/analysis , Neurons/enzymology , Neuroprotective Agents/pharmacology , Nitric Oxide Synthase/analysis , Nitric Oxide Synthase Type II , Oxidation-Reduction , Polymerase Chain Reaction , Rats , Rats, Inbred Lew , T-Lymphocyte Subsets/drug effects , Tyrosine/analysis , Uric Acid/pharmacology , Virus Replication/drug effectsABSTRACT
Infection of immunocompetent adult rats with Borna disease virus (BDV) causes severe encephalitis and neural dysfunction. The expression of COX-2 and CGRP, genes previously shown to be implicated in CNS disease and peripheral inflammation, was dramatically upregulated in the cortical neurons of acutely BDV-infected rats. Neuronal COX-2 and CGRP upregulation was predominantly seen in brain areas where ED1-positive macrophages/microglia accumulated. In addition, COX-2 expression was strongly induced in brain endothelial cells and the number of COX-2 immunoreactive microglial cells was increased. In contrast, despite increased expression of viral antigens, neither COX-2 nor CGRP expression was altered in the CNS of BDV-infected rats treated with dexamethasone, or tolerant to BDV. Thus, increased CGRP and COX-2 expression in the BDV-infected brain is the result of the inflammatory response and likely to be involved in the pathogenesis of virus-induced encephalitis.
