The central nervous system inflammatory response to neurotropic virus infection is peroxynitrite dependent.
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.
Hooper
D C
DC
Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107, USA. douglas.c.hooper@mail.tju.edu
Kean
R B
RB
Scott
G S
GS
Spitsin
S V
SV
Mikheeva
T
T
Morimoto
K
K
Bette
M
M
Röhrenbeck
A M
AM
Dietzschold
B
B
Weihe
E
E
D000208:Acute Disease; D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001890:Borna Disease / Q000276:immunology* / Q000473:pathology / Q000821:virology; D001891:Borna disease virus / Q000276:immunology* / Q000502:physiology; D001921:Brain / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D001923:Brain Chemistry / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D018792:Encephalitis, Viral / Q000276:immunology* / Q000473:pathology / Q000821:virology; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use*; D005609:Free Radicals; D020869:Gene Expression Profiling; D007121:Immunocompetence; D007249:Inflammation; D018655:Lymphocyte Count; D009419:Nerve Tissue Proteins / Q000032:analysis; D009474:Neurons / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000032:analysis; D052247:Nitric Oxide Synthase Type II; D010084:Oxidation-Reduction; D030421:Peroxynitrous Acid / Q000502:physiology*; D016133:Polymerase Chain Reaction; D051381:Rats; D011917:Rats, Inbred Lew; D016176:T-Lymphocyte Subsets / Q000187:drug effects; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis; D014527:Uric Acid / Q000494:pharmacology / Q000627:therapeutic use*; D014779:Virus Replication / Q000187:drug effects
D000956:Antigens, Viral; D016166:Free Radical Scavengers; D005609:Free Radicals; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D030421:Peroxynitrous Acid; D014527:Uric Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat