Innate but not adaptive immune responses contribute to behavioral seizures following viral infection.
OBJECTIVE
To examine the role of innate immunity in a novel viral infection-induced seizure model.


METHODS
C57BL/6 mice, mouse strains deficient in interleukin (IL)-1RI, IL-6, tumor necrosis factor (TNF)-RI, or myeloid differentiation primary response gene 88 (MyD88), or transgenic mice (OT-I) were infected with Theiler's murine encephalomyelitis virus (TMEV) or were mock infected. Mice were followed for acute seizures. Tissues were examined for neuron loss, the presence of virus (viral RNA and antigen), perivascular cuffs, macrophages/microglia, and gliosis, and mRNA expression of IL-1, TNF-alpha, and IL-6.


RESULTS
IL-1 does not play a major role in seizures, as IL-1RI- and MyD88-deficient mice displayed a comparable seizure frequency relative to controls. In contrast, TNF-alpha and IL-6 appear to be important in the development of seizures, as only 10% and 15% of TNF-RI- and IL-6-deficient mice, respectively, showed signs of seizure activity. TNF-alpha and IL-6 mRNA levels also increased in mice with seizures. Inflammation (perivascular cuffs, macrophages/microglia, and gliosis) was greater in mice with seizures. OT-I mice (virus persists) had a seizure rate that was comparable to controls (no viral persistence), thereby discounting a role for TMEV-specific T cells in seizures.


CONCLUSIONS
We have implicated the innate immune response to viral infection, specifically TNF-alpha and IL-6, and concomitant inflammatory changes in the brain as contributing to the development of acute seizures. This model is a potential infection-driven model of mesial temporal lobe epilepsy with hippocampal sclerosis.
Kirkman
Nikki J
NJ
Department of Pathology, University of Utah, Salt Lake City, Utah 84132, USA.
Libbey
Jane E
JE
Wilcox
Karen S
KS
White
H Steve
HS
Fujinami
Robert S
RS
D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000276:immunology / Q000473:pathology; D018188:Cardiovirus Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000276:immunology; D005911:Gliosis / Q000276:immunology / Q000473:pathology; D006624:Hippocampus / Q000276:immunology / Q000473:pathology; D007113:Immunity, Innate / Q000276:immunology*; D015850:Interleukin-6 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012640:Seizures / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D017945:Theilovirus / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C490125:Gadd45b protein, mouse; D000097642:GADD45 Proteins