Abstract
Reovirus is a nonenveloped mammalian virus that provides a useful model system for studies of viral infections in the young. Following internalization into host cells, the outermost capsid of reovirus virions is removed by endosomal cathepsin proteases. Determinants of capsid disassembly kinetics reside in the viral σ3 protein. However, the contribution of capsid stability to reovirus-induced disease is unknown. In this study, we found that mice inoculated intramuscularly with a serotype 3 reovirus containing σ3-Y354H, a mutation that reduces viral capsid stability, succumbed at a higher rate than those infected with wild-type virus. At early times after inoculation, σ3-Y354H virus reached higher titers than wild-type virus at several sites within the host. Animals inoculated perorally with a serotype 1 reassortant reovirus containing σ3-Y354H developed exaggerated myocarditis accompanied by elaboration of pro-inflammatory cytokines. Surprisingly, unchallenged littermates of mice infected with σ3-Y354H virus displayed higher titers in the intestine, heart, and brain than littermates of mice inoculated with wild-type virus. Together, these findings suggest that diminished capsid stability enhances reovirus replication, dissemination, lethality, and host-to-host spread, establishing a new virulence determinant for nonenveloped viruses.
Highlights
Penetration of a target cell membrane is an essential requirement for infection by all viruses
Viral capsid stability balances on a fulcrum, as viruses must be sufficiently stable in the environment to reach the host yet uncoat efficiently once the target cell barrier has been breached
Reoviruses are useful models to understand the relationship between viral entry and pathogenesis
Summary
Penetration of a target cell membrane is an essential requirement for infection by all viruses. Enveloped viruses use structural rearrangements of specialized proteins to drive fusion of the viral envelope and host membranes. Nonenveloped viruses often encode proteins that disrupt host membranes in response to cues imparted by target cells, such as receptor binding, endosomal acidification, or proteolytic cleavage. For other viruses, including adenoviruses and reoviruses, receptor binding and membrane bypass occur at different cellular sites and are mediated by distinct viral proteins [17,18,19,20,21]. Structural rearrangement or partial disassembly of the virion is often required to promote interactions with a target cell membrane. Despite its importance in cell entry and replication, the contribution of capsid stability to viral pathogenesis is poorly understood
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