Role of IFN-γ in an experimental murine model of West Nile virus-induced seizures

• Published in: Journal of neurochemistry 2007-11, Vol.103 (3), p.1019-1030
• Main Authors: Getts, Daniel R, Matsumoto, Izuru, Müller, Marcus, Getts, Meghann Teague, Radford, Jane, Shrestha, Bimmi, Campbell, Iain L, King, Nicholas J.C
• Format: Article
• Language: English
• Subjects: Animals; Brain - immunology; Brain - physiopathology; Brain - virology; Cercopithecus aethiops; Convulsants - pharmacology; cytokines; Disease Models, Animal; Excitatory Amino Acid Antagonists - pharmacology; excitotoxicity; Female; Genetic Predisposition to Disease - genetics; glutamate; Glutamic Acid - metabolism; Interferon-gamma - genetics; Interferon-gamma - immunology; Interleukin-6 - immunology; Interleukin-6 - metabolism; Limbic Encephalitis - genetics; Limbic Encephalitis - immunology; Limbic Encephalitis - virology; limbic system; Mice; Mice, Inbred C57BL; Mice, Knockout; Neural Pathways - immunology; Neural Pathways - physiopathology; Neural Pathways - virology; Receptors, N-Methyl-D-Aspartate - agonists; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; seizure development; Seizures - genetics; Seizures - immunology; Seizures - virology; Synaptic Transmission - genetics; Synaptic Transmission - immunology; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - metabolism; Vero Cells; viral encephalitis; West Nile Fever - complications; West Nile Fever - immunology; West Nile Fever - physiopathology; West Nile virus
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2007.04798.x

Seizures are a major complication of viral encephalitis. However, the mechanisms of seizure-associated neuronal dysfunction remain poorly understood. We report that intranasal inoculation with West Nile virus (WNV) (Sarafend) causes limbic seizures in C57BL/6 mice, but not in interferon (IFN)-γ-deficient (IFN-γ⁻/⁻) mice. Both strains showed similar levels of virus in the brain, as well as similar concentrations of the cytokines, tumor necrosis factor and interleukin-6, both of which can alter neuronal excitability. Experiments in chimeric IFN-γ⁻/⁻ mice reconstituted with IFN-γ-producing leukocytes showed that IFN-γ is not required during central nervous system infection for limbic seizure development, suggesting a role for IFN-γ in the developing brain. This was supported responses to pentylenetetrazole, kainic acid (KA), and N-methyl- d-aspartate (NMDA). Both strains of mice exhibited similar behavior after pentylenetetrazole challenge. However, while NMDA and KA treatment resulted in characteristic seizures in C57BL/6 mice, these responses were diminished (NMDA treatment) or absent (KA treatment) in IFN-γ⁻/⁻ mice. Furthermore, NMDA-receptor blockade with MK-801 in WNV-infected C57BL/6 mice abrogated seizures and prolonged survival. Our data show that IFN-γ plays an important role in the development of the excitatory seizure pathways in the brain and that these cascades become pathogenic in encephalitic WNV infection.