Diminished Reovirus Capsid Stability Alters Disease Pathogenesis and Littermate Transmission

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.

Author Summary

Following attachment and internalization, viruses disassemble to complete the entry process, establish infection, and cause disease. Viral capsid stability balances on a fulcrum, as viruses must be sufficiently stable in the environment to reach the host yet also uncoat efficiently once the target cell barrier has been breached. Reoviruses are useful models to understand the relationship between viral entry and pathogenesis. Residues within reovirus outer-capsid protein σ3 influence capsid stability, but the function of capsid stability in disease pathogenesis was not known. We found that serotype 1 and serotype 3 reovirus variants with diminished capsid stability attributable to a single amino change in σ3 displayed enhanced lethality in newborn mice following peroral and intramuscular inoculation, respectively. In the serotype 1 background, this variant caused increased damage to cardiac tissue and increased elaboration of inflammatory mediators in comparison to wild-type virus. Remarkably, diminished capsid stability also enhanced the spread of virus between inoculated and uninoculated littermates. Taken together, these findings define a new virulence determinant for reovirus and shed light on general principles of viral pathogenesis for nonenveloped viruses.