Reovirus Activates a Caspase-Independent Cell Death Pathway

Berger, Angela K.; Danthi, Pranav

Analogous to studies on reovirus-induced apoptosis (14, 20, 21) , we found no effect of inhibition of necroptosis on reovirus replication (see Fig. S2 in the supplemental material). Thus, regardless of whether reovirus induces necroptosis in other cultured cell lines, the physiological relevance of necroptosis to reovirus infection can be determined only by in vivo experiments, as has been necessary for the demonstration of the pathogenic role of reovirus-induced apoptosis (7-12, 14-16, 59) . T3 reoviruses cause bile duct injury, leading to biliary atresia (60) (61) (62) (63) . Histological examination of the reovirus-infected bile ducts has revealed the presence of necrotic tissue (61, 62) . Some studies on reovirusinduced myocarditis also report the presence of necrotic lesions (12, 13, 64) . Consistent with the induction of the necrotic form of cell death, inflammatory cells are detected in the injured tissues (12, 13, 61, 62) . In each of these cases, it is not clear if the necrotic tissue observed is secondary necrosis as a consequence of apoptosis or whether direct induction of necrosis contributes to cell death in these tissues. In at least two of these studies (12, 13) , cell death in the infected tissue appears to occur even in the absence of molecules previously shown to be required for apoptosis in cultured cells (20, 26) , suggesting the existence of alternate mechanisms of cell death. Further work is needed to determine whether this alternate form of cell death is indeed necrotic and occurs via a caspase-independent, RIP1-dependent pathway that we have identified here. Such studies will enhance our understanding of reovirus pathogenesis. The two forms of programmed cell death pathways observed following reovirus infection, apoptosis and necroptosis, are part of the intrinsic host defense response (1, 2) . Analogous to a few other viruses (65) (66) (67) (68) (69) (70) (71) (72) (73) , apoptosis following reovirus infection is activated prior to synthesis of the viral RNA by the proteinaceous components of the incoming viral capsid (15, 16, 19, 49) . Though there are fewer studies that indicate how necroptosis is initiated following virus infection, extant information and our findings presented here indicate that necroptosis is initiated later in infection following synthesis of new viral genomes or gene products (53, (74) (75) (76) . Based on these findings, we propose that apoptosis and necroptosis are two complementary mechanisms that sense and respond to different stages of pathogen invasion with a common goal of limiting viral infection through cellular suicide.