STAT3 Mediates Resistance to Pseudorabies Virus Infection in a Phosphorylation-Dependent Manner

Pseudorabies virus (PRV) imposes heavy economic burdens on the worldwide pig industry.STAT3 is a well-established regulator of antiviral immunity; however, its functional roles and underlying mechanisms during PRV infection remain poorly defined.Here, we observed that PRV infection robustly induces STAT3 phosphorylation.We further characterized the functional contribution of STAT3 to PRV replication.Our results demonstrated that knockdown of STAT3 markedly facilitates PRV replication, whereas overexpression of wild-type STAT3 (STAT3 WT ) significantly suppresses viral replication.Consistently, the constitutively active STAT3 (STAT3 D661V ) inhibits PRV replication, while the dominant-negative mutant STAT3 (STAT3 Y705F ) strongly enhances viral replication.In vivo assays further confirmed that PRV replication is greatly elevated in STAT3 Y705F/+ mice.Mechanistically, STAT3 modulates PRV replication by positively regulating critical innate antiviral genes, including IFITM1, IFIT2, and ISG15.STAT3 knockdown reduces the expression of these genes; conversely, overexpression of STAT3 WT or STAT3 D661V elevates them, and disruption of STAT3 Y705 diminishes their expression.Moreover, STAT3 modulates the production of the pro-inflammatory cytokine interleukin-6 (IL-6) upon PRV infection.Collectively, these findings reveal that STAT3-mediated innate immune responses are essential for host defense against PRV infection, highlighting its capacity to restrict PRV replication via regulating antiviral genes expression and IL-6 production.