Mechanisms Involved in Virus-Induced Neural Cell Death
Abstract
We are using experimental infection with reoviruses as a model to study how viruses induce cell death (apoptosis) and cause dysregulation of the cell cycle, and the significance of these events on viral pathogenesis in vivo. We have developed this into one of the most fully characterized systems for understanding viral and cellular mechanisms of both apoptosis and cell cycle dysregulation. We have shown that apoptosis is a critical part of tissue injury in vivo in both experimental models of virus-induced CNS injury (encephalitis) and cardiac injury (myocarditis). Our in vitro studies indicate that reovirus-induced apoptosis involves the tumor necrosis factor receptor (TNFR) super family and specifically death receptors 4 and 5 (DR4, DR5) and their ligand (TRAIL). Apoptosis involves both death-receptor (DR) and mitochondrial-associated cell death pathways, and leads to the early activation of initiator caspases 8 and 9, followed by activation of effector caspase 3 and cleavage of caspase-dependent cellular substrates. Caspase-8 dependent cleavage of the pro-apoptotic Bcl-2 family protein Bid is required for cytosolic release of cytochrome C and the subsequent apoptosome-mediated activation of caspase 9. Reovirus-induced DR-initiated apoptosis requires participation of the mitochondrial signaling pathways for its optimal expression. In addition to inducing apoptosis, infection results in dysregulation of the normal cell cycle. This results from a G2/M phase arrest which requires the viral sigma-ls protein and is associated with inhibition of the activity of the key G2 to M checkpoint transition kinase p34cdc2.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2001
- Accession Number
- ADA398123
Entities
People
- Kenneth L. Tyler
Organizations
- University of Colorado Health