Caspase 3-dependent cell death of neurons contributes to the pathogenesis of West Nile virus encephalitis.
West Nile virus (WNV) is a neurotropic, arthropod-borne flavivirus that has become a significant global cause of viral encephalitis. To examine the mechanisms of WNV-induced neuronal death and the importance of apoptosis in pathogenesis, we evaluated the role of a key apoptotic regulator, caspase 3. WNV infection induced caspase 3 activation and apoptosis in the brains of wild-type mice. Notably, congenic caspase 3(-/-) mice were more resistant to lethal WNV infection, although there were no significant differences in the tissue viral burdens or the kinetics of viral spread. Instead, decreased neuronal death was observed in the cerebral cortices, brain stems, and cerebella of caspase 3(-/-) mice. Analogously, primary central nervous system (CNS)-derived neurons demonstrated caspase 3 activation and apoptosis after WNV infection, and treatment with caspase inhibitors or a genetic deficiency in caspase 3 significantly decreased virus-induced death. These studies establish that caspase 3-dependent apoptosis contributes to the pathogenesis of lethal WNV encephalitis and suggest possible novel therapeutic targets to restrict CNS injury.
Samuel
Melanie A
MA
Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, Campus Box 8051, 660 S. Euclid Avenue, St. Louis, MO 63110, USA.
Morrey
John D
JD
Diamond
Michael S
MS
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D053148:Caspase 3 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D018792:Encephalitis, Viral / Q000209:etiology* / Q000473:pathology; D004789:Enzyme Activation; D019084:Fluorescent Antibody Technique, Indirect; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000473:pathology* / Q000821:virology; D019562:Viral Load; D014901:West Nile Fever / Q000209:etiology / Q000473:pathology; D014902:West Nile virus / Q000235:genetics / Q000472:pathogenicity*
D053148:Caspase 3