The Reovirus σ1s Protein Is a Determinant of Hematogenous but Not Neural Virus Dissemination in Mice

Nonstructural protein sigma 1s is a critical determinant of hematogenous dissemination by type 1 reoviruses, which reach the central nervous system (CNS) by a strictly blood-borne route. However, it is not known whether sigma 1s contributes to neuropathogenesis of type 3 reoviruses, which disseminate by both vascular and neural pathways. Using isogenic type 3 viruses that vary only in sigma 1s expression, we observed that mice survived at a higher frequency following hind-limb inoculation with sigma 1s-null virus than when inoculated with wild-type virus. This finding suggests that sigma 1s is essential for reovirus virulence when inoculated at a site that requires systemic spread to cause disease. Wild-type and sigma 1s-null viruses produced comparable titers in the spinal cord, suggesting that sigma 1s is dispensable for invasion of the CNS. Although the two viruses ultimately achieved similar peak titers in the brain, loads of wild-type virus were substantially greater than those of the sigma 1s-null mutant at early times after inoculation. In contrast, wild-type virus produced substantially higher titers than the sigma 1s-null virus in peripheral organs to which reovirus spreads via the blood, including the heart, intestine, liver, and spleen. Concordantly, viral titers in the blood were higher following infection with wild-type virus than following infection with the sigma 1s-null mutant. These results suggest that differences in viral brain titers at early time points postinfection are due to limited virus delivery to the brain by hematogenous pathways. Transection of the sciatic nerve prior to hind-limb inoculation diminished viral spread to the spinal cord. However, wild-type virus retained the capacity to disseminate to the brain following sciatic nerve transection, indicating that wild-type reovirus can spread to the brain by the blood. Together, these results indicate that sigma 1s is not required for reovirus spread by neural mechanisms. Instead, sigma 1s mediates hematogenous dissemination within the infected host, which is required for full reovirus neurovirulence.