Independent regulation of reovirus membrane penetration and apoptosis by the μ1 φ domain

Abstract

Apoptosis plays an important role in the pathogenesis of reovirus encephalitis. Reovirus outer-capsid protein μ1, which functions to penetrate host cell membranes during viral entry, is the primary regulator of apoptosis following reovirus infection. Ectopic expression of full-length and truncated forms of μ1 indicates that the μ1 φ domain is sufficient to elicit a cell death response. To evaluate the contribution of the μ1 φ domain to the induction of apoptosis following reovirus infection, φ mutant viruses were generated by reverse genetics and analyzed for the capacity to penetrate cell membranes and elicit apoptosis. We found that mutations in φ diminish reovirus membrane penetration efficiency by preventing conformational changes that lead to generation of key reovirus entry intermediates. Independent of effects on membrane penetration, amino acid substitutions in φ affect the apoptotic potential of reovirus, suggesting that φ initiates apoptosis subsequent to cytosolic delivery. In comparison to wild-type virus, apoptosis-defective φ mutant viruses display diminished neurovirulence following intracranial inoculation of newborn mice. These results indicate that the φ domain of μ1 plays an important regulatory role in reovirus-induced apoptosis and disease. © 2008 Danthi et al.