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

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 1-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 1 protein functions to pierce endosomal membranes during this temporal window, these findings point to an important role for 1 in activating signaling pathways that lead to apoptosis. To understand mechanisms used by 1 to induce apoptosis, a panel of 1 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 ␦ region of 1 reduce the efficiency of membrane penetration. These mutations also diminish the capacities of reovirus to activate proapoptotic transcription factors NF-B and IRF-3 and elicit apoptosis. Additionally, we observed that following intracranial inoculation, an apoptosis-deficient 1 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 1 in evoking prodeath signaling pathways that regulate reovirus pathogenesis.

Apoptosis Induced by Mammalian Reovirus Is Beta Interferon (IFN) Independent and Enhanced by IFN Regulatory Factor 3- and NF-κB-Dependent Expression of Noxa

“…However, both Bid-deficient mice and caspase-3-deficient mice exhibit decreased reovirus replication in the CNS (7,24). Similarly, a reovirus mutant that displays normal replication but a reduced capacity to induce apoptosis in cultured cells produces lower yields in the CNS of infected mice (22). Together, these results suggest that apoptosis is required for efficient replication in vivo.…”

“…However, mechanisms by which these proteins become activated, and the specific functions of IRF-3 and NF-B in this process, remain unclear. Reovirus mutants that induce diminished levels of apoptosis display attenuated virulence in the murine central nervous system (CNS), indicating a predominant role for apoptosis in reovirus pathogenicity (22,23). This conclusion is strengthened by the finding that reovirus neurovirulence is diminished in NF-B p50-deficient mice (57).…”

Epizootic Hemorrhagic Disease Virus Induces and Benefits from Cell Stress, Autophagy, and Apoptosis

“…The present study mainly employs the Ibaraki strain of EHDV2 (EHDV2-IBA), originally isolated from infected cattle in 1959, in Ibaraki, Japan (8). Selected experiments were also carried out with EHDV7-Israel (EHDV7-ISR), isolated from infected cattle in 2006 in Israel (1).For different types of reoviruses, including BTV, apoptosis is integral to the cellular pathogenesis they induce (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Yet the molecular mechanisms that govern reovirus-mediated induction of apoptosis are a contentious matter (10,17,19,20).…”

Mice immunogenicity after vaccination by DNA vaccines containing individual genes of a new type of reovirus

“…important for virus control. M2 is a virulence gene and could contribute to the marked differences found between reovirus strains (Coffey et al, 2006;Danthi et al, 2008;Hrdy et al, 1982;Rubin and Fields, 1980); M2 could also directly affect the ability of reovirus to cause disease after introduction into the gastrointestinal tract. The S1 and M2 genes are involved in receptor binding and penetrating the host cell membrane and could determine the capacity of different reovirus strains to induce apoptosis (Clarke et al, 2001).…”