Targeted Prostaglandin E2 Inhibition Enhances Antiviral Immunity through Induction of Type I Interferon and Apoptosis in Macrophages

Aspirin gained tremendous popularity during the 1918 Spanish Influenza virus pandemic, 50 years prior to the demonstration of their inhibitory action on prostaglandins. Here, we show that during influenza A virus (IAV) infection, prostaglandin E-2 (PGE(2)) was upregulated, which led to the inhibition of type I interferon (IFN) production and apoptosis in macrophages, thereby causing an increase in virus replication. This inhibitory role of PGE(2) was not limited to innate immunity, because both antigen presentation and T cell mediated immunity were also suppressed. Targeted PGE(2) suppression via genetic ablation of microsomal prostaglandin E-synthase 1 (mPGES-1) or by the pharmacological inhibition of PGE(2) receptors EP2 and EP4 substantially improved survival against lethal IAV infection whereas PGE(2) administration reversed this phenotype. These data demonstrate that the mPGES-1-PGE(2) pathway is targeted by IAV to evade host type I IFN-dependent antiviral immunity. We propose that specific inhibition of PGE(2) signaling might serve as a treatment for IAV.