Caspase-3 activation is required for reovirus-induced encephalitis <Emphasis Type="Italic">in vivo</Emphasis> |
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Authors: | J David Beckham Kathryn D Tuttle " target="_blank">Kenneth L Tyler |
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Institution: | (1) Laboratory of Chemotherapy, Rega Institute, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000, Leuven, Belgium;(2) Division of Morphology and Molecular Pathology, University Hospitals, Minderbroedersstraat 12, B-3000, Leuven, Belgium;(3) Laboratory of Immunobiology, Rega Institute, Katholieke Universiteit, Minderbroedersstraat 10, B-3000, Leuven, Belgium;(4) Experimental Laboratory Medicine, University Hospitals, Herestaat 49, B-3000, Leuven, Belgium |
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Abstract: | Reovirus infection of neonatal mice provides a classic experimental system for understanding the molecular pathogenesis of
central nervous system (CNS) viral infection. CNS tissue injury, caused by many human neurotropic viruses, including herpes
viruses and West Nile virus, is associated with caspase-dependent apoptotic neuronal cell death. We have previously shown
that reovirus-induced CNS tissue injury results from apoptosis and is associated with activation of both death-receptor and
mitochondrial apoptotic pathways culminating in the activation of the downstream effector caspase, caspase-3. In order to
directly investigate the role of caspase-3 in virus-induced neuronal death and CNS tissue injury during encephalitis, we have
compared the pathogenesis of reovirus CNS infection in mice lacking the caspase-3 gene (caspase-3 (−/−)) to syngeneic wild-type mice. Prior studies of antiapoptotic treatments for reovirus-infected mice have indicated that protection
from reovirus-induced neuronal injury can occur without altering the viral titer in the brains of infected mice. We now show
that reovirus infection of caspase-3 (−/−) mice was associated with dramatic reduction in severity of CNS tissue injury, decreased viral antigen and titer in the brain,
and enhanced survival of infected mice. Following intracerebral inoculation, the authors also show that virus spread from
the brain to the eyes in reovirus-infected caspase-3 (−/−) mice, indicating that viral spread was intact in these mice. Examination of brains of long-term survivors of reovirus infection
among caspase-3 (−/−) mice showed that these mice eventually clear their CNS viral infection, and do not manifest residual or delayed CNS tissue
injury. |
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