Mammalian reoviruses infect cells in the central nervous system (CNS) of newborn mice, leading to apoptosis and lethal encephalitis. Reovirus-induced apoptosis requires engagement of cell-surface receptors, intracellular signaling, and activation of transcription factor NF-kappaB. Experiments are proposed to identify viral and cellular determinants of reovirus-induced apoptosis and elucidate the significance of this host-cell response in vivo. The central hypothesis of the proposed research is that NF-kappaB activation and apoptosis are required for reovirus-induced CNS disease.
In Specific Aim 1, steps in reovirus replication that lead to NF-kappaB activation and apoptosis will be defined.
In Specific Aim 2, intracellular signaling events required for reovirus-induced NF-kappaB activation and apoptosis will be identified.
In Specific Aim 3, the role of NF-kappaB activation and apoptosis in reovirus virulence will be investigated. These experiments will provide an enhanced understanding of how viruses perturb host-cell-signaling pathways to cause cell death and disease. Information gained from these studies should foster development of new antiviral strategies designed to inhibit apoptosis.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Virology Study Section (VR)
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Cassetti, Cristina
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Vanderbilt University Medical Center
Schools of Medicine
United States
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