Reovirus Activates a Caspase-Independent Cell Death Pathway

Berger, Angela K.; Danthi, Pranav

In a variety of cell lines, prototype type T3 reovirus strains, T3D and T3A, induce significantly more apoptosis than the type T1 reovirus strain T1L (30) (31) (32) (33) (34) . In this study, we investigated how T3 and T1 reovirus strains differ in their capacity to evoke cell death. We found that T3D activates NF-B, initiator caspases, and effector caspases to a greater extent than T1L. Unexpectedly, when T3D-induced NF-B activation was inhibited, it did not diminish cell death. Caspase inhibitors also failed to block reovirus-induced cell death. Blockade of the kinase activity of RIP1 resulted in a reduction in cell death. Because reovirus-induced cell death in L929 cells fulfills all the criteria that are used to describe necroptosis-activation of death signaling, dispensability of active caspases, the requirement for RIP1 kinase activity, diminishment of cellular ATP levels, and membrane permeability of dying cells (3)-our findings indicate that reovirus is also capable of killing cells by necroptosis. Moreover, we found that induction of this form of cell death following reovirus infection requires de novo synthesis of viral mRNA and proteins. These studies therefore highlight a second mechanism by which reovirus infection interfaces with host signal transduction pathways to evoke cell death.