title: PAR1 contributes to influenza A virus pathogenicity in mice.
abstract: Influenza causes substantial morbidity and mortality, and highly pathogenic and drug-resistant strains are likely to emerge in the future. Protease-activated receptor 1 (PAR1) is a thrombin-activated receptor that contributes to inflammatory responses at mucosal surfaces. The role of PAR1 in pathogenesis of virus infections is unknown. Here, we demonstrate that PAR1 contributed to the deleterious inflammatory response after influenza virus infection in mice. Activating PAR1 by administering the agonist TFLLR-NH2 decreased survival and increased lung inflammation after influenza infection. Importantly, both administration of a PAR1 antagonist and PAR1 deficiency protected mice from infection with influenza A viruses (IAVs). Treatment with the PAR1 agonist did not alter survival of mice deficient in plasminogen (PLG), which suggests that PLG permits and/or interacts with a PAR1 function in this model. PAR1 antagonists are in human trials for other indications. Our findings suggest that PAR1 antagonism might be explored as a treatment for influenza, including that caused by highly pathogenic H5N1 and oseltamivir-resistant H1N1 viruses.
authors.affiliation: Virologie et Pathologie Humaine, EA 4610, Université Lyon1, Faculté de Médecine RTH Laennec, Lyon, France.
authors.forename: Khaled
authors.initials: K
authors.lastname: Khoufache
authors.forename: Fatma
authors.initials: F
authors.lastname: Berri
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Nacken
authors.forename: Annette B
authors.initials: AB
authors.lastname: Vogel
authors.forename: Marie
authors.initials: M
authors.lastname: Delenne
authors.forename: Eric
authors.initials: E
authors.lastname: Camerer
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Coughlin
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Bruno
authors.initials: B
authors.lastname: Lina
authors.forename: Guus F
authors.initials: GF
authors.lastname: Rimmelzwaan
authors.forename: Oliver
authors.initials: O
authors.lastname: Planz
authors.forename: Stephan
authors.initials: S
authors.lastname: Ludwig
authors.forename: Béatrice
authors.initials: B
authors.lastname: Riteau
mesh_terms: D000818:Animals; D004285:Dogs; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000472:pathogenicity*; D053124:Influenza A Virus, H5N1 Subtype / Q000472:pathogenicity*; D007251:Influenza, Human / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D009842:Oligopeptides / Q000494:pharmacology; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D010958:Plasminogen / Q000235:genetics / Q000276:immunology; D044463:Receptor, PAR-1 / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D010975:Platelet Aggregation Inhibitors
chemical_list: D009842:Oligopeptides; C462999:PAR-1-activating peptide; D044463:Receptor, PAR-1; D010958:Plasminogen; D010975:Platelet Aggregation Inhibitors