Role of IFN-gamma in an experimental murine model of West Nile virus-induced seizures.
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)-gamma-deficient (IFN-gamma-/-) 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-gamma-/- mice reconstituted with IFN-gamma-producing leukocytes showed that IFN-gamma is not required during central nervous system infection for limbic seizure development, suggesting a role for IFN-gamma 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-gamma-/- mice. Furthermore, NMDA-receptor blockade with MK-801 in WNV-infected C57BL/6 mice abrogated seizures and prolonged survival. Our data show that IFN-gamma 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.
Getts
Daniel R
DR
The Discipline of Pathology, The University of Sydney, Sydney, New South Wales, Australia.
Matsumoto
Izuru
I
Müller
Marcus
M
Getts
Meghann Teague
MT
Radford
Jane
J
Shrestha
Bimmi
B
Campbell
Iain L
IL
King
Nicholas J C
NJ
D000818:Animals; D001921:Brain / Q000276:immunology* / Q000503:physiopathology / Q000821:virology*; D002522:Chlorocebus aethiops; D003292:Convulsants / Q000494:pharmacology; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D020363:Limbic Encephalitis / Q000235:genetics / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009434:Neural Pathways / Q000276:immunology / Q000503:physiopathology / Q000821:virology; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D012640:Seizures / Q000235:genetics / Q000276:immunology* / Q000821:virology*; D009435:Synaptic Transmission / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D014709:Vero Cells; D014901:West Nile Fever / Q000150:complications / Q000276:immunology* / Q000503:physiopathology
D003292:Convulsants; D018691:Excitatory Amino Acid Antagonists; D015850:Interleukin-6; D016194:Receptors, N-Methyl-D-Aspartate; D014409:Tumor Necrosis Factor-alpha; D018698:Glutamic Acid; D007371:Interferon-gamma