Novel strategy for treatment of viral central nervous system infection by using a cell-permeating inhibitor of c-Jun N-terminal kinase.
Viral encephalitis is a major cause of morbidity and mortality worldwide, yet there is no proven efficacious therapy for most viral infections of the central nervous system (CNS). Many of the viruses that cause encephalitis induce apoptosis and activate c-Jun N-terminal kinase (JNK) following infection. We have previously shown that reovirus infection of epithelial cell lines activates JNK-dependent apoptosis. We now show that reovirus infection resulted in activation of JNK and caspase-3 in the CNS. Treatment of reovirus-infected mice with a cell-permeating peptide that competitively inhibits JNK activity resulted in significantly prolonged survival of intracerebrally infected mice following an otherwise lethal challenge with T3D (100 x 50% lethal dose). Protection correlated with reduced CNS injury, reduced neuronal apoptosis, and reduced c-Jun activation without altering the viral titer or viral antigen distribution. Given the efficacy of the inhibitor in protecting mice from viral encephalitis, JNK inhibition represents a promising and novel treatment strategy for viral encephalitis.
Beckham
J David
JD
Department of Medicine, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA.
Goody
Robin J
RJ
Clarke
Penny
P
Bonny
Christophe
C
Tyler
Kenneth L
KL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002490:Central Nervous System / Q000201:enzymology* / Q000473:pathology / Q000821:virology; D018792:Encephalitis, Viral / Q000201:enzymology / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012089:Mammalian orthoreovirus 3 / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000201:enzymology / Q000473:pathology / Q000821:virology; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D012088:Reoviridae Infections / Q000201:enzymology / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*
D004791:Enzyme Inhibitors; D010455:Peptides; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3