Apoptotic cell death is a common cellular response to viral infection; however, mechanisms by which viruses elicit apoptosis are poorly understood. Mammalian reoviruses have served as useful models for studies of viral pathogenesis. Reoviruses induce apoptosis in cultured cells and in the murine central nervous system. Strain-specific differences in the capacity to induce apoptosis are determined primarily by the viral S1 gene. The S1 gene encodes two proteins, viral attachment protein σ1 and non-structural protein σ1s. Results presented in this thesis demonstrate that expression of σ1s is not required for reovirus-induced apoptosis, indicating that σ1 is the S1 gene-product responsible for mediating strain-specific differences in apoptosis induction. Linkage of the viral attachment protein with the magnitude of the apoptotic response led to the hypothesis that reovirus engagement of cellular receptors elicits signaling events required for apoptosis. Experiments described in this thesis demonstrate that reovirus activates NF-κB, a transcription factor involved regulating cellular stress responses, and that NF-κB activation is required for reovirus-induced apoptosis of cultured cells and in vivo. Binding of σ1 to both cell-surface sialic acid and junction adhesion molecule was found to be required to achieve maximal levels of apoptosis induction following reovirus infection. Finally, studies reported in this thesis demonstrate that viral disassembly of virions to form infectious subvirion particles (ISVPs) is an absolute requirement for reovirus to elicit apoptosis and that viral disassembly must occur within the same cellular compartment as receptor engagement to achieve this cellular response. Together, these findings suggest a model in which binding of reovirus ISVPs to cellular receptors initiates signals required to both activate NF-κB and induce apoptosis.
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