Mechanisms of Virus-Induced Neural Cell Death
Abstract
We are using post-mortem and brain-biopsy derived material from patients with herpes simplex and varicella zoster virus encephalitis to identify the presence of apoptotic cells in the cNS and their correlation with viral infection and tissue injury. We are also using reovirus infection as a model to study cellular mechanisms of virus-induced cell death. Reovirus infection is associated with the activation of the nuclear transcription factor NF-kB, and inhibition of this activation inhibits apoptosis. There is increased expression of the apoptosis inducing ligand mAIL in reovirus-infected cells. inhibition of binding to its cell surface death receptors, DR4 and DRS, inhibits reovirus-induced apoptosis. mRNA levels of mAIL and DR4 are increased in reovirus-infected cells, as are levels of mature DRS protein. Reovirus infection is associated with activation of apoptosis-associated proteases including calpain and caspases. Caspase activation involves the death-receptor associated (caspase-8) and the mitochondrial-associated (caspase 9) apoptotic pathways. Inhibition of either calpain or caspase activation inhibits reovirus-induced apoptosis in vitro. In a murine model of reovirus-induced myocarditis, inhibition of calpain activation prevents apoptotic myocardial injury. This suggests that inhibition of apoptosis may be a novel strategy for anti-viral therapy. Reovirus-induced apoptosis and cell cycle dysregulation are both determined by the viral Si gene. Reoviruses induce a G2M cell cycle arrest The Si-encoded sigma1s protein is necessary for this process, but is not essential for apoptosis. Reovirus-induced apoptosis can be inhibited without preventing G2M cell cycle arrest, indicating that apoptosis-associated DNA damage does not cause reovirus-induced cell cycle arrest.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2000
- Accession Number
- ADA384857
Entities
People
- Kenneth L. Tyler
Organizations
- University of Colorado Health