Novel Strategy for Treatment of Viral Central Nervous System Infection by Using a Cell-Permeating Inhibitor of c-Jun N-Terminal Kinase

Abstract

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؋ 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.

Reovirus Activates Transforming Growth Factor β and Bone Morphogenetic Protein Signaling Pathways in the Central Nervous System That Contribute to Neuronal Survival following Infection

“…8). These results echo our prior studies in which we used an in vivo pharmacologic inhibitor of JNK activation that resulted in reduced cell death and tissue injury with no significant decrease in viral titer (2). These data suggest that viral replication and virus-induced cell death can be disassociated and that successful therapy of viral encephalitis will require inhibition of both viral replication and virus-induced cell death.…”

“…Previous studies have also demonstrated that virus-induced signaling events affect cell survival and cell death. Reovirus-induced selective activation of mitogen-activated protein kinases such as c-Jun N-terminal kinase (JNK) are vital to apoptosis in vitro and in a murine model of reovirus-induced encephalitis (2,9). Similarly, the activation and subsequent inhibition of NF-B signaling are important determinants of apoptosis (5,7,10).…”

Apoptosis Induced by Mammalian Reovirus Is Beta Interferon (IFN) Independent and Enhanced by IFN Regulatory Factor 3- and NF-κB-Dependent Expression of Noxa

“…The removal of any of the upstream components of these pathways can alter the efficiency of cell death but is unlikely to completely abrogate the response. Since apoptosis is a primary component of the pathogenesis of reovirus infection in the CNS (55) and heart (28,57), and the inhibition of these pathways was suggested previously to be a possible therapeutic strategy for viral encephalitis and myocarditis (6,28,66), these results suggest that interventions must be targeted at later events in apoptosis induction, such as caspase-3 activation, for full efficacy.…”

Daxx Upregulation within the Cytoplasm of Reovirus-Infected Cells Is Mediated by Interferon and Contributes to Apoptosis

“…We have previously shown that JNK activation correlates strongly with reovirus-induced apoptosis (10,16,17). Notably, pharmacologic JNK inhibition decreases neuronal apoptosis and enhances survival of reovirus-infected mice (10).…”

“…These strains specifically infect neurons and induce neurologic injury via induction of caspase 3-dependent apoptosis (4)(5)(6)(7)(9)(10)(11)(12). Several members of the death receptor family, including TRAIL and Fas, are known to mediate reovirus-induced apoptosis in both in vitro and in vivo settings (7,(13)(14)(15).…”