Characterization of Plaque-Sized Variants of Daniel's (DA) Strain in Theiler's Virus-Induced Epilepsy

Epilepsy is a complex neurological disease characterized by recurrent seizures. Patients with viral encephalitis have a 16-fold increased risk of developing epilepsy, and this risk can persist for about 15 years after the occurrence of initial viral infection. Theiler's murine encephalomyelitis virus (TMEV) infection induces a well-characterized experimental model of epilepsy in C57BL/6 mice. In response to intracerebral (I.C.) injection of Daniel's (DA) strain of TMEV, there is vigorous immune response, which is detrimental to neurons and contributes to acute seizures, rendering mice susceptible to epilepsy. A comparative in vivo challenge study with either one of the two variants of the DA strain, small (DA-D_S) or large (DA-C_L) plaque forming variants, revealed differences in the diseases they induced in C57BL/6 mice. Compared to DA-C_L-, DA-D_S-infected mice exhibited significantly more seizures, higher clinical scores, neuroinflammation, and neuronal damage (mainly in the CA1-CA2 regions of hippocampus). Moreover, the brains of DA-D_S infected mice contained approximately five-fold higher virus than those of DA-C_L infected mice. A sequence comparison of the DA-C_L and DA-D_S genome sequences showed mutations in the leader (L) and L* proteins of DA-C_L variant, which may be the cause of attenuating phenotype of DA-C_L variant in the C57BL/6 mouse model of epilepsy.