Lymphatic Type 1 Interferon Responses Are Critical for Control of Systemic Reovirus Dissemination

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. Nonstructural 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 interferon-alpha receptor (IFNAR1) signaling. 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. IMPORTANCE Type 1 interferons (IFN-1) are critical host responses to viral infection. However, the contribution of IFN-1 responses to control of viruses in specific cell and tissue types is not fully defined. Here, we identify IFN-1 responses in lymphatics as important for limiting reovirus dissemination. We found that nonstructural protein sigma 1s enhances reovirus resistance to IFN-1 responses, as a reovirus mutant lacking sigma 1s was more sensitive to IFN-1 than wild-type virus. In neonatal mice, sigma 1s is required for reovirus systemic spread. We used tissue-specific IFNAR1 deletion in combination with the IFN-1-sensitive sigma 1s-null reovirus as a tool to test how IFN-1 responses in lymphatics affect reovirus systemic spread. Deletion of IFNAR1 in lymphatic cells using Cre-lox technology enabled dissemination of the IFN-1-sensitive sigma 1s-deficient reovirus. Together, our results indicate that IFN-1 responses in lymphatics are critical for controlling reovirus systemic spread.

Automated summary

The nonstructural protein sigma 1s is crucial for efficient replication of reovirus in cells, while lymphatic type 1 interferon (IFN-1) responses play a key role in limiting reovirus systemic dissemination. Deleting IFNAR1 in lymphatic cells enables the spread of an IFN-1-sensitive sigma 1s-deficient reovirus, indicating the importance of IFN-1 responses in lymphatics for controlling reovirus systemic spread.