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

• DOI: 10.1016/j.immuni.2014.02.013
• Publication Date: 2014-04-10T17:15:10Z
• Authors: François Coulombe; Joanna Jaworska; Mark Verway; Fanny Tzelepis; Amir Massoud; Joshua Gillard; Gary Wong; Gary Kobinger; Zhou Xing; Christian Couture; Philippe Joubert; Jörg H. Fritz; William S. Powell; Maziar Divangahi
• Keywords: T-Lymphocytes; Immunology; Apoptosis; Dinoprostone; Mice; 03 medical and health sciences; Orthomyxoviridae Infections; Immunology and Allergy; Animals; Molecular Targeted Therapy; Cells, Cultured; Prostaglandin-E Synthases; Mice, Knockout; Antigen Presentation; 0303 health sciences; Macrophages; Immunity; Receptors, Prostaglandin E, EP2 Subtype; 3. Good health; Intramolecular Oxidoreductases; Mice, Inbred C57BL; Infectious Diseases; Gene Expression Regulation; Influenza A virus; Interferon Type I; Receptors, Prostaglandin E, EP4 Subtype

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 E2 (PGE2) 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 PGE2 was not limited to innate immunity, because both antigen presentation and T cell mediated immunity were also suppressed. Targeted PGE2 suppression via genetic ablation of microsomal prostaglandin E-synthase 1 (mPGES-1) or by the pharmacological inhibition of PGE2 receptors EP2 and EP4 substantially improved survival against lethal IAV infection whereas PGE2 administration reversed this phenotype. These data demonstrate that the mPGES-1-PGE2 pathway is targeted by IAV to evade host type I IFN-dependent antiviral immunity. We propose that specific inhibition of PGE2 signaling might serve as a treatment for IAV.