Lymphatic type-1 interferon responses are critical for control of systemic reovirus dissemination

Abstract

Mammalian orthoreovirus (reovirus) spreads from the site of infection to every organ system in the body via the blood. However, mechanisms that underlie reovirus hematogenous spread remain undefined. Non-structural protein {sigma}1s is a critical determinant of reovirus bloodstream dissemination that is required for efficient viral replication in many types of cultured cells. Here, we used the specificity of the {sigma}1s protein for promoting hematogenous spread as a platform to uncover a role for lymphatic type-1 interferon (IFN-1) responses in limiting reovirus systemic dissemination. We found that replication of a {sigma}1s-deficient reovirus was restored to wild-type levels in cells with defective type-1 interferon a-receptor (IFNAR1) signaling. In vivo, reovirus spreads systemically following oral inoculation of neonatal mice, whereas the {sigma}1s-null virus remains localized to the intestine. We found that {sigma}1s enables reovirus spread in the presence of a functional IFN-1 response, as the {sigma}1s-deficient reovirus disseminated comparably to wild-type virus in IFNAR1-/- mice. Lymphatics are hypothesized to mediate reovirus spread from the intestine to the bloodstream. IFNAR1 deletion from cells expressing lymphatic vessel endothelium receptor-1 (LYVE-1), a marker for lymphatic endothelial cells, enabled the {sigma}1s-deficient reovirus to disseminate systemically. Together, our findings indicate that IFN-1 responses in lymphatics limit reovirus dissemination. Our data further suggest that the lymphatics are an important conduit for reovirus hematogenous spread. IMPORTANCEType-1 interferon (IFN-1) responses are a critical component of the host response to viral infections. However, the contribution of specific cell and tissue types to control of viral infections is not known. Here, we found that reoviruses lacking nonstructural protein were more sensitive to IFN-1 responses than wild-type reovirus, indicating that {sigma}1s is important for reovirus resistance to IFN-1 responses. The {sigma}1s protein also is a key determinant of reovirus systemic spread. We used tissue-specific IFNAR1 deletion in combination with the IFN-1-sensitive {sigma}1s-null reovirus as a tool to identify a role for lymphatics in reovirus dissemination. We used Cre-lox technology to delete type-1 interferon a-receptor (IFNAR1) in lymphatic cells and found that the IFN-1-sensitive {sigma}1s-deficient reovirus disseminated in mice with lymphatic endothelial cells-specific deletion of IFNAR1. Together, our results indicate that IFN-1 responses in lymphatics are critical for controlling reovirus systemic spread.