Reovirus Apoptosis and Virulence Are Regulated by Host Cell Membrane Penetration Efficiency

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Abstract
Apoptosis plays an important role in the pathogenesis of reovirus encephalitis and myocarditis in infected animals. Differences in apoptosis efficiency displayed by reovirus strains are linked to the viral μ1-encoding M2 gene segment. Studies using pharmacologic inhibitors of reovirus replication demonstrate that apoptosis induction by reovirus requires viral disassembly in cellular endosomes but not RNA synthesis. Since the μ1 protein functions to pierce endosomal membranes during this temporal window, these findings point to an important role for μ1 in activating signaling pathways that lead to apoptosis. To understand mechanisms used by μ1 to induce apoptosis, a panel of μ1 mutant viruses generated by reverse genetics was analyzed for the capacities to penetrate host cell membranes, activate proapoptotic signaling pathways, evoke cell death, and produce encephalitis in newborn mice. We found that single amino acid changes within the δ region of μ1 reduce the efficiency of membrane penetration. These mutations also diminish the capacities of reovirus to activate proapoptotic transcription factors NF-κB and IRF-3 and elicit apoptosis. Additionally, we observed that following intracranial inoculation, an apoptosis-deficient μ1 mutant is less virulent in newborn mice in comparison to the wild-type virus. These results indicate a critical function for the membrane penetration activity of μ1 in evoking prodeath signaling pathways that regulate reovirus pathogenesis.