Peter Charles McMinn
Telethon Institute for Child Health Research; Perth,
Australia
Flavivirus encephalitis is a serious disease with high case
fatality rates and high rates of residual neurological sequelae among
survivors. Studies of fatal human cases and data derived from animal models
have provided conflicting evidence for the pathogenesis of flavivirus
encephalitis, suggesting that disease may be caused either by virus-mediated
cytopathology or by immunopathology. It is important to understand the
pathogenesis of flavivirus encephalitis in order to design effective control
and prevention strategies. We have studied the pathogenesis of flavivirus
encephalitis using the Murray Valley
encephalitis virus – mouse model and have shown that flavivirus encephalitis is
primarily an immunopathological disease induced by viral infection of neurons
within specific regions of the central nervous system (CNS) and resulting from
marked inflammatory responses within the CNS. Furthermore, we have shown that
the flavivirus envelope (E) glycoprotein contains critical determinants of
neuroinvasiveness in mice. Mutations introduced into the envelope gene by
site-directed mutagenesis of a Murray
Valley encephalitis virus
infectious cDNA clone results in the rescue of attenuated strains that have
potential as live attenuated vaccines. Furthermore, we have shown that the
attenuation of these strains is linked to altered fusion function of the
mutated enveloped glycoprotein.