title: Targeted prostaglandin E2 inhibition enhances antiviral immunity through induction of type I interferon and apoptosis in macrophages.
abstract: 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.
authors.affiliation: Department of Medicine, Department of Microbiology & Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre and Research Institute, Meakins-Christie Laboratories, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Coulombe
authors.affiliation: Department of Medicine, Department of Microbiology & Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre and Research Institute, Meakins-Christie Laboratories, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada.
authors.forename: Joanna
authors.initials: J
authors.lastname: Jaworska
authors.affiliation: Department of Medicine, Department of Microbiology & Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre and Research Institute, Meakins-Christie Laboratories, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Verway
authors.affiliation: Department of Medicine, Department of Microbiology & Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre and Research Institute, Meakins-Christie Laboratories, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada.
authors.forename: Fanny
authors.initials: F
authors.lastname: Tzelepis
authors.affiliation: Department of Medicine, Department of Microbiology & Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre and Research Institute, Meakins-Christie Laboratories, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada.
authors.forename: Amir
authors.initials: A
authors.lastname: Massoud
authors.affiliation: Department of Medicine, Department of Microbiology & Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre and Research Institute, Meakins-Christie Laboratories, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada.
authors.forename: Joshua
authors.initials: J
authors.lastname: Gillard
authors.affiliation: Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB R3E 3R2, Canada.
authors.forename: Gary
authors.initials: G
authors.lastname: Wong
authors.affiliation: Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, MB R3E 3R2, Canada.
authors.forename: Gary
authors.initials: G
authors.lastname: Kobinger
authors.affiliation: McMaster Immunology Research Centre and Department of Pathology and Molecular Medicine, McMaster University, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Xing
authors.affiliation: Department of Pathology, Centre Hospitalier Universitaire de Québec, Hôtel-Dieu de Québec, 11 côte du Palais, Quebec, Quebec G1R 2J6, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Couture
authors.affiliation: Department of Pathology, Centre Hospitalier Universitaire de Québec, Hôtel-Dieu de Québec, 11 côte du Palais, Quebec, Quebec G1R 2J6, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Joubert
authors.affiliation: Department of Microbiology & Immunology, McGill Life Sciences Complex, Complex Traits Group, Bellini Pavilion, 3649 Promenade Sir William Osler, Montreal, Quebec H3G 0B1, Canada.
authors.forename: Jörg H
authors.initials: JH
authors.lastname: Fritz
authors.affiliation: Department of Medicine, Department of Microbiology & Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre and Research Institute, Meakins-Christie Laboratories, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada.
authors.forename: William S
authors.initials: WS
authors.lastname: Powell
authors.affiliation: Department of Medicine, Department of Microbiology & Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre and Research Institute, Meakins-Christie Laboratories, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada. Electronic address: maziar.divangahi@mcgill.ca.
authors.forename: Maziar
authors.initials: M
authors.lastname: Divangahi
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D015232:Dinoprostone / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D007109:Immunity / Q000187:drug effects / Q000235:genetics; D009980:Influenza A virus / Q000502:physiology*; D007370:Interferon Type I / Q000235:genetics / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors* / Q000235:genetics; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000276:immunology; D000071876:Prostaglandin-E Synthases; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000037:antagonists & inhibitors; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D014779:Virus Replication / Q000235:genetics
chemical_list: D007370:Interferon Type I; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone