Reovirus Activates a Caspase-Independent Cell Death Pathway

Berger, Angela K.; Danthi, Pranav

These data indicate that in addition to apoptosis, reovirus is also capable of inducing necroptosis following viral infection. We also found that induction of the necroptosis pathway following reovirus infection occurs later in infection and requires the de novo synthesis of viral RNA or proteins. RIP1-dependent necroptosis pathways are initiated via at least three different mechanisms. One pathway for initiation of necroptosis is dependent on death receptor signaling (50) . Experiments presented here and in several other studies indicate that death receptor signaling is activated following reovirus infection (14, 22, 51) . While this observation may suggest that necroptosis following reovirus infection may be a consequence of death receptor signaling, our findings using the IKK inhibitor, which fails to inhibit necroptosis despite blocking classical apoptotic pathways, argues against this idea. An alternate pathway for the induction of necroptosis involves recognition of pathogen-associated molecular patterns by pattern recognition receptors. Among these, TLR3, a sensor of dsRNA, and DNA-dependent activator of interferon regulatory factor (DAI), a sensor of dsDNA, have been implicated in initiating necroptosis following viral infection (52, 53) . Based on the requirement for viral genomic RNA and for viral replication, our data may suggest a role for TLR3-mediated detection of viral RNA in induction of necroptosis in these cells. If so, it remains to be determined how viral genomic RNA within the reovirus core or viral mRNA, which is present in the cytoplasm, may be detected by endosomally localized TLR3. A third pathway for necroptosis is thought to occur independently from Toll-like receptor (TLR) or death receptor signaling and requires the loss of inhibitors of apoptosis (IAPs) (52) . Interestingly, there is evidence for the loss of IAPs during reovirus infection (25) . Thus, it is possible that necroptosis following reovirus infection may be initiated by any of these pathways. It is also possible that one of the eleven reovirus proteins synthesized by translation of viral mRNA triggers this death response. Our ongoing studies are targeted toward understanding how necroptosis is triggered by reovirus infection and how strains T3D and T1L differ in their capacity to evoke necroptosis.