Host Factor PLA2G2A Strengthens Innate Immune Defense Against Coronaviruses Through Activation of the TBK1–IRF3 Pathway

Coronaviruses, including porcine deltacoronavirus (PDCoV), pose a sustained threat to livestock production and public health, yet the mechanisms underlying coronavirus–host interactions remain incompletely defined. Here, we performed ileal transcriptomic profiling of piglets infected with in vitro–passaged PDCoV strains (P0, P100, P200) and found that most differentially expressed genes (DEGs) were associated with innate immune regulation. Among them, Phospholipase A2 Group IIA (PLA2G2A) displayed markedly altered intestinal expression across viral passages. Functional assays demonstrated that PLA2G2A restricts PDCoV infection and enhances host innate immunity. Mechanistically, PLA2G2A directly interacted with TANK-binding kinase 1 (TBK1), promoting its phosphorylation and subsequent activation of interferon regulatory factor 3 (IRF3), thereby augmenting type I interferon (IFNβ) production and interferon-stimulated gene (ISG) expression. Inhibition of TBK1 activity abrogated both the antiviral and immunostimulatory functions of PLA2G2A. Furthermore, PLA2G2A exhibited antiviral effects against porcine epidemic diarrhea virus (PEDV) and infectious bronchitis virus (IBV), which were lost in IFN-deficient Vero cells, indicating strict dependence on an intact type I interferon pathway. Collectively, our findings identify PLA2G2A as a key activator of innate antiviral immunity through the TBK1–IRF3–IFNβ axis and highlight its potential as a broad-spectrum antiviral factor against coronaviruses.