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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.
Highlights
Neurological disease is one of the most serious manifestations of viral infection
Many viruses produce central nervous system disease by infecting and systematically killing host neurons via a process known as programmed cell death, or apoptosis
For most viruses, it is not understood how viral invasion is detected by host cells nor how this recognition triggers a signaling cascade that leads to apoptotic cell death
Summary
Neurological disease is one of the most serious manifestations of viral infection. A diverse group of neurotropic viruses including alphaviruses, bunyaviruses, flaviviruses, herpesviruses, and rhabdoviruses are capable of causing encephalitis. Central nervous system (CNS) disease following infection by many of these viruses is associated with neuronal apoptosis [1,2,3,4,5]. Mammalian reoviruses are highly tractable models for analysis of virus-host interactions. Studies using these viruses have provided significant insights into mechanisms by which viruses initiate proapoptotic signaling responses that contribute to the pathogenesis of viral encephalitis. Following infection of newborn mice, reoviruses disseminate systemically, producing injury to a variety of organs, including the CNS, heart, and liver [6]. Infection of mice with type 3 reovirus results in fatal encephalitis [7,8,9], which is associated with extensive apoptosis at sites of viral replication [10,11,12]. Modulation of apoptosis in infected animals using pharmacological inhibitors or through genetic means attenuates CNS disease, highlighting an important contributory role of apoptosis to the pathogenesis of encephalitis [11,12,13,14]
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