Reovirus nonstructural protein σ1s is required for establishment of viremia and systemic dissemination

Serotype-specific patterns of reovirus disease in the CNS of newborn mice segregate with the viral S1 gene segment, which encodes attachment protein sigma 1 and nonstructural protein sigma 1s. The importance of receptor recognition in target cell selection by reovirus implicates the sigma 1 protein as the primary effector of disease outcome. However, the contribution of sigma 1s to reovirus disease is unknown. To define the function of sigma 1s in reovirus pathogenesis, we generated a sigma 1s-deficient virus by altering a single nucleotide to disrupt the sigma 1s translational start site. Viruses were recovered that contain nine gene segments from strain type 3 Dearing and either the wild-type or sigma 1s-null S1 gene segment from strain type 1 Lang. Following peroral inoculation of newborn mice, both viruses replicated in the intestine, although the wildtype virus achieved higher yields than the sigma 1s-null virus. However, unlike the wild-type virus, the sigma 1s-deficient virus failed to disseminate to sites of secondary viral replication, including the brain, heart, and liver. Within the small intestine, both viruses were detected in Peyer's patches, but only the wild-type virus reached the mesenteric lymph node. Concordantly, wild-type virus, but not sigma 1s-deficient virus, was detected in the blood of infected animals. Wild-type and sigma 1s-null viruses produced equivalent titers following intracranial inoculation, indicating that sigma 1s is dispensable for viral growth in the murine CNS. These results suggest a key role for sigma 1s in virus spread from intestinal lymphatics to the bloodstream, thereby allowing the establishment of viremia and dissemination to sites of secondary replication within the infected host.