Mechanisms of Virus-Induced Neural Cell Death
Final rept. 15 Aug 1998-14 Feb 2005
COLORADO UNIV HEALTH SCIENCES CENTER DENVER
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We have used experimental infection with reoviruses to study how viruses induce cell death apoptosis, and the significance of apoptosis in the pathogenesis of viral infection. We have developed one of the best characterized experimental models for investigating and manipulating viral cell death pathways. We have shown that apoptosis is a major mechanism of reovirus-induced cell death in murine models of key human viral infections including myocarditis and encephalitis. We have shown that inhibiting apoptosis can reduce the degree of virus-induced injury in target organs and prolong the survival of infected animals. In virus infected cells apoptosis is initiated by the activation of death receptors, and its full expression requires augmentation by mitochondrial pro-apoptotic factors including SmacDIABLO. We have identified the pro-apoptotic Bcl-2 family protein Bid as a key intermediary between the death receptor and mitochondrial apoptotic pathways. We have shown that reovirus infection induces the selective activation and up-regulation of both mitogen activated protein kinase MAPK cascades and transcription factor pathways including those involving JNK, c-Jun and NF-kappaB. We have used oligonucleotide microarrays to study reovirus-induced changes in gene expression in infected host cells.
- Medicine and Medical Research