Key result
Blocking caspases with z-VAD-fmk combined with SeV mutant Fctr48z infection completely abrogated the cytopathic effect, demonstrating two separate mechanisms of cell death during SeV F infection.
Sendai virus strain F induces apoptosis via both TIAR and caspase-dependent mechanisms, which can be simultaneously blocked by a mutated viral leader RNA and caspase inhibitors.
Dual cell death pathways in SeV F infection merit targeted antiviral exploration; leaves open clinical translation pending in vivo validation.
Induction of apoptosis during Sendai virus (SeV) infection has previously been documented to be triggered by initiator caspases (for strain F) or by a contribution of the cellular protein TIAR (T-cell-activated intracellular antigen-related) (for strain Z). Here, evidence was provided that both TIAR and caspases are simultaneously involved in apoptosis induction as a result of infection with SeV strain F. SeV F infection induced death in all tested cell lines, which could only be partially prevented through the pan-caspase inhibitor z-VAD-fmk. However, infection of seven different cell lines with the SeV mutant Fctr48z overexpressing a TIAR-sequestering RNA from the modified leader resulted in a cell type-dependent reduced cytopathic effect (CPE); in an earlier study a similar mutant derived from SeV Z was shown to prevent the induction of any CPE. Finally, blocking of caspases through z-VAD-fmk combined with Fctr48z infection led to complete abrogation of CPE, clearly demonstrating the existence of two separate mechanisms inducing cell death during SeV F infections. Interestingly, a cell type-specific interference between these two mechanisms could be detected during infection with the mutant virus Fctr48z: RNA transcribed from the mutated leader was able to trans-dominantly inhibit caspase-mediated apoptosis. Thus, virus-expressed factors enabling a well-balanced ratio of suppression and triggering of apoptosis seem to be essential for optimal virus replication.
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Wiegand et al. (2005) studied Sendai virus infection. SeV mutant Fctr48z and pan-caspase inhibitor z-VAD-fmk vs. SeV strain F infection alone was evaluated on Cytopathic effect (CPE) and apoptosis induction. Blocking caspases with z-VAD-fmk combined with SeV mutant Fctr48z infection completely abrogated the cytopathic effect, demonstrating two separate mechanisms of cell death during SeV F infection.
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