2’-5’ Oligoadenylate Synthetase-Like 1- (OASL1-) deficient mice promote antiviral protection against pseudorabies virus infection associated with enhanced production of type I interferon

Pseudorabies virus (PRV) infects various mammals and causes Aujeszky’s disease, posing a significant threat to the pig industry. The interaction between PRV and the host’s innate immune system, however, remains poorly understood. The interferon (IFN)-stimulated gene (ISG), 2’-5’ oligoadenylate synthetase-like 1 (OASL1), possesses antiviral properties and modulates type I IFN production by inhibiting the translation of IFN regulatory factor 7 (IRF7). This study explored the role of OASL1 in the host’s response to pseudorabies virus (PRV) infection using OASL1-deficient (Oasl1^−/−) mice. The results showed that PRV infection significantly increased OASL1 expression in bone marrow-derived dendritic cells, macrophages, and various organs, including the spleen, lung, and brain, of wild-type (WT) mice. In contrast, Oasl1^−/− mice showed significantly milder clinical symptoms and fewer histopathological lesions after PRV infection compared to WT mice, which suffered severe neurological symptoms and succumbed with 100% mortality. Additionally, Oasl1^−/− mice had substantially lower PRV viral loads in the spleen and reduced levels of pro-inflammatory cytokines in multiple organs. Notably, PRV-infected Oasl1^−/− mice demonstrated significantly higher levels of IRF7 protein in the spleen, lung, and brain, accompanied by increased secretion of type I IFNs. Mechanistically, IRF7 knockdown in Oasl1^−/− macrophages reversed the enhanced type I IFN response and restored viral replication, confirming that the antiviral phenotype conferred by OASL1 deficiency is functionally dependent on the IRF7 axis. These findings suggest that OASL1 negatively regulates antiviral immunity against PRV by suppressing IRF7-mediated type I IFN responses. Modulating OASL1 activity may thus represent a promising strategy to bolster host defense against PRV and related viral infections.