The severity of Murray Valley encephalitis in mice is linked to neutrophilinfiltration and inducible nitric oxide synthase activity in the central nervous system

A study of immunopathology in the central nervous system (CNS) during infec tion with a virulent strain of Murray Valley encephalitis virus (MVE) in we anling Swiss mice following peripheral inoculation is presented. It has pre viously been shown that virus enters the murine CNS 4 days after peripheral inoculation, spreads to the anterior olfactory nucleus, the pyriform corte x, and the hippocampal formation at 5 days postinfection (p.i.), and then s preads throughout the cerebral cortex, caudate putamen, thalamus, and brain stem between 6 and 9 days p.i. (P. C. McMinn, L. Dalgarno, and R. C, Weir, Virology 220:414-423, 1996). Here we show that the encephalitis which deve lops in MVE-infected mice from 5 days p.i. is associated with the developme nt of a neutrophil inflammatory response in perivascular regions and in the CNS parenchyma. Infiltration of neutrophils into the CNS was preceded by i ncreased expression of tumor necrosis factor alpha and the neutrophil-attra cting chemokine N51/KC within the CNS. Depletion of neutrophils with a cyto toxic monoclonal antibody (RB6-8C5) resulted in prolonged survival and decr eased mortality in MVE-infected mice. In addition, neutrophil infiltration and disease onset correlated with expression of the enzyme-inducible nitric oxide synthase (iNOS) within the CNS, Inhibition of iNOS by aminoguanidine resulted in prolonged survival and decreased mortality in MVE-infected mic e. This study provides strong support for the hypothesis that Murray Valley encephalitis is primarily an immunopathological disease.